Sequence and domain conservation of the coelacanth Hsp40 and Hsp90 chaperones suggests conservation of function
- Tastan Bishop, Özlem, Edkins, Adrienne L, Blatch, Gregory L
- Authors: Tastan Bishop, Özlem , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/126932 , vital:35936 , https://doi.10.1002/jez.b.22541
- Description: Molecular chaperones and their associated co‐chaperones play an important role in preserving and regulating the active conformational state of cellular proteins. The chaperone complement of the Indonesian Coelacanth, Latimeria menadoensis, was elucidated using transcriptomic sequences. Heat shock protein 90 (Hsp90) and heat shock protein 40 (Hsp40) chaperones, and associated cochaperones were focused on, and homologous human sequences were used to search the sequence databases. Coelacanth homologs of the cytosolic, mitochondrial and endoplasmic reticulum (ER) homologs of human Hsp90 were identified, as well as all of the major co‐chaperones of the cytosolic isoform. Most of the human Hsp40s were found to have coelacanth homologs, and the data suggested that all of the chaperone machinery for protein folding at the ribosome, protein translocation to cellular compartments such as the ER and protein degradation were conserved. Some interesting similarities and differences were identified when interrogating human, mouse, and zebrafish homologs. For example, DnaJB13 is predicted to be a non‐functional Hsp40 in humans, mouse, and zebrafish due to a corrupted histidine‐proline‐aspartic acid (HPD) motif, while the coelacanth homolog has an intact HPD. These and other comparisons enabled important functional and evolutionary questions to be posed for future experimental studies.
- Full Text:
- Date Issued: 2014
- Authors: Tastan Bishop, Özlem , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2014
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/126932 , vital:35936 , https://doi.10.1002/jez.b.22541
- Description: Molecular chaperones and their associated co‐chaperones play an important role in preserving and regulating the active conformational state of cellular proteins. The chaperone complement of the Indonesian Coelacanth, Latimeria menadoensis, was elucidated using transcriptomic sequences. Heat shock protein 90 (Hsp90) and heat shock protein 40 (Hsp40) chaperones, and associated cochaperones were focused on, and homologous human sequences were used to search the sequence databases. Coelacanth homologs of the cytosolic, mitochondrial and endoplasmic reticulum (ER) homologs of human Hsp90 were identified, as well as all of the major co‐chaperones of the cytosolic isoform. Most of the human Hsp40s were found to have coelacanth homologs, and the data suggested that all of the chaperone machinery for protein folding at the ribosome, protein translocation to cellular compartments such as the ER and protein degradation were conserved. Some interesting similarities and differences were identified when interrogating human, mouse, and zebrafish homologs. For example, DnaJB13 is predicted to be a non‐functional Hsp40 in humans, mouse, and zebrafish due to a corrupted histidine‐proline‐aspartic acid (HPD) motif, while the coelacanth homolog has an intact HPD. These and other comparisons enabled important functional and evolutionary questions to be posed for future experimental studies.
- Full Text:
- Date Issued: 2014
STAT3 interacts directly with Hsp90:
- Prinsloo, Earl, Kramer, Adam H, Edkins, Adrienne L, Blatch, Gregory L
- Authors: Prinsloo, Earl , Kramer, Adam H , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2012
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165142 , vital:41212 , DOI: 10.1002/iub.607
- Description: Heat shock protein 90 (Hsp90) functionally modulates signal transduction. The signal transducer and activator of transcription 3 (STAT3) mediates interleukin‐6 family cytokine signaling. Aberrant activation and mutation of STAT3 is associated with oncogenesis and immune disorders, respectively. Hsp90 and STAT3 have previously been shown to colocalize and coimmunoprecipitate in common complexes.
- Full Text:
- Date Issued: 2012
- Authors: Prinsloo, Earl , Kramer, Adam H , Edkins, Adrienne L , Blatch, Gregory L
- Date: 2012
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165142 , vital:41212 , DOI: 10.1002/iub.607
- Description: Heat shock protein 90 (Hsp90) functionally modulates signal transduction. The signal transducer and activator of transcription 3 (STAT3) mediates interleukin‐6 family cytokine signaling. Aberrant activation and mutation of STAT3 is associated with oncogenesis and immune disorders, respectively. Hsp90 and STAT3 have previously been shown to colocalize and coimmunoprecipitate in common complexes.
- Full Text:
- Date Issued: 2012
STIP1/HOP regulates the actin cytoskeleton through interactions with actin and changes in actin-binding proteins cofilin and profilin:
- Beckley, Samantha Joy, Hunter, Morgan C, Kituyi, Sarah N, Wingate, Ianthe, Chakraborty, Abantika, Schwarz, Kelly, Makhubu, Matodzi P, Rousseau, Robert P, Ruck, Duncan K, de la Mare, Jo-Anne, Blatch, Gregory L, Edkins, Adrienne L
- Authors: Beckley, Samantha Joy , Hunter, Morgan C , Kituyi, Sarah N , Wingate, Ianthe , Chakraborty, Abantika , Schwarz, Kelly , Makhubu, Matodzi P , Rousseau, Robert P , Ruck, Duncan K , de la Mare, Jo-Anne , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165373 , vital:41238 , https://doi.org/10.3390/ijms21093152
- Description: Cell migration plays a vital role in both health and disease. It is driven by reorganization of the actin cytoskeleton, which is regulated by actin-binding proteins cofilin and profilin. Stress-inducible phosphoprotein 1 (STIP1) is a well-described co-chaperone of the Hsp90 chaperone system, and our findings identify a potential regulatory role of STIP1 in actin dynamics. We show that STIP1 can be isolated in complex with actin and Hsp90 from HEK293T cells and directly interacts with actin in vitro via the C-terminal TPR2AB-DP2 domain of STIP1, potentially due to a region spanning two putative actin-binding motifs. We found that STIP1 could stimulate the in vitro ATPase activity of actin, suggesting a potential role in the modulation of F-actin formation. Interestingly, while STIP1 depletion in HEK293T cells had no major effect on total actin levels, it led to increased nuclear accumulation of actin, disorganization of F-actin structures, and an increase and decrease in cofilin and profilin levels, respectively. This study suggests that STIP1 regulates the cytoskeleton by interacting with actin, or via regulating the ratio of proteins known to affect actin dynamics.
- Full Text:
- Date Issued: 2020
- Authors: Beckley, Samantha Joy , Hunter, Morgan C , Kituyi, Sarah N , Wingate, Ianthe , Chakraborty, Abantika , Schwarz, Kelly , Makhubu, Matodzi P , Rousseau, Robert P , Ruck, Duncan K , de la Mare, Jo-Anne , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165373 , vital:41238 , https://doi.org/10.3390/ijms21093152
- Description: Cell migration plays a vital role in both health and disease. It is driven by reorganization of the actin cytoskeleton, which is regulated by actin-binding proteins cofilin and profilin. Stress-inducible phosphoprotein 1 (STIP1) is a well-described co-chaperone of the Hsp90 chaperone system, and our findings identify a potential regulatory role of STIP1 in actin dynamics. We show that STIP1 can be isolated in complex with actin and Hsp90 from HEK293T cells and directly interacts with actin in vitro via the C-terminal TPR2AB-DP2 domain of STIP1, potentially due to a region spanning two putative actin-binding motifs. We found that STIP1 could stimulate the in vitro ATPase activity of actin, suggesting a potential role in the modulation of F-actin formation. Interestingly, while STIP1 depletion in HEK293T cells had no major effect on total actin levels, it led to increased nuclear accumulation of actin, disorganization of F-actin structures, and an increase and decrease in cofilin and profilin levels, respectively. This study suggests that STIP1 regulates the cytoskeleton by interacting with actin, or via regulating the ratio of proteins known to affect actin dynamics.
- Full Text:
- Date Issued: 2020
Targeting conserved pathways as a strategy for novel drug development: disabling the cellular stress response:
- Edkins, Adrienne L, Blatch, Gregory L
- Authors: Edkins, Adrienne L , Blatch, Gregory L
- Date: 2012
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/165129 , vital:41211 , ISBN 978-3-642-28174-7 , DOI: 10.1007/978-3-642-28175-4_4
- Description: The ability to respond to and cope with stress at a molecular level is essential for cell survival. The stress response is conserved across organisms by the expression of a group of molecular chaperones known as heat shock proteins (HSP). HSP are ubiquitous and highly conserved proteins that regulate cellular protein homeostasis and trafficking under physiological and stressful conditions, including diseases such as cancer and malaria. HSP are good drug targets for the treatment of human diseases, as the significant functional and structural data available suggest that they are essential for cell survival and that, despite conservation across species, there are biophysical and biochemical differences between HSP in normal and disease states that allow HSP to be selectively targeted. In this chapter, we review the international status of this area of research and highlight progress by us and other African researchers towards the characterisation and targeting of HSP from humans and parasites from Plasmodium and Trypanosoma as drug targets.
- Full Text:
- Date Issued: 2012
- Authors: Edkins, Adrienne L , Blatch, Gregory L
- Date: 2012
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/165129 , vital:41211 , ISBN 978-3-642-28174-7 , DOI: 10.1007/978-3-642-28175-4_4
- Description: The ability to respond to and cope with stress at a molecular level is essential for cell survival. The stress response is conserved across organisms by the expression of a group of molecular chaperones known as heat shock proteins (HSP). HSP are ubiquitous and highly conserved proteins that regulate cellular protein homeostasis and trafficking under physiological and stressful conditions, including diseases such as cancer and malaria. HSP are good drug targets for the treatment of human diseases, as the significant functional and structural data available suggest that they are essential for cell survival and that, despite conservation across species, there are biophysical and biochemical differences between HSP in normal and disease states that allow HSP to be selectively targeted. In this chapter, we review the international status of this area of research and highlight progress by us and other African researchers towards the characterisation and targeting of HSP from humans and parasites from Plasmodium and Trypanosoma as drug targets.
- Full Text:
- Date Issued: 2012
The African coelacanth genome provides insights into tetrapod evolution:
- Amemiya, Chris T, Alföldi, Jessica, Lee, Alison P, Fan, Shaohua, Philippe, Herve´, MacCallum, Iain, Braasch, Ingo, Manousaki, Tereza, Schneider, Igor, Rohner, Nicolas, Organ, Chris, Chalopin, Domitille, Smith, Jeramiah J, Robinson, Mark, Dorrington, Rosemary A, Gerdol, Marco, Aken, Bronwen, Biscotti, Maria Assunta, Barucca, Marco, Baurain, Denis, Berlin, Aaron, Blatch, Gregory L, Buonocore, Francesco, Burmester, Thorsten, Campbell, Michael S, Canapa, Adriana, Cannon, John P, Christoffels, Alan, De Moro, Gianluca, Edkins, Adrienne L, Fan, Lin, Fausto, Anna Maria, Feiner, Nathalie, Forconi, Mariko, Gamieldien, Junaid, Gnerre, Sante, Gnirke, Andreas, Goldstone, Jared V, Haerty, Wilfried, Hahn, Mark E, Hesse, Uljana, Hoffmann, Steve, Johnson, Jeremy, Karchner, Sibel I, Kuraku, Shigehiro, Lara, Marcia, Levin, Joshua Z, Litman, Gary W, Mauceli, Evan, Miyake, Tsutomu, Mueller, M Gail, Nelson, David R, Nitsche, Anne, Olmo, Ettore, Ota, Tatsuya, Pallavicini, Alberto, Panji, Sumir, Picone, Barbara, Ponting, Chris P, Prohaska, Sonja J, Przybylski, Dariusz, Ratan Saha, Nil, Ravi, Vydianathan, Ribeiro, Filipe J, Sauka-Spengler, Tatjana, Scapigliati, Giuseppe, Searle, Stephen M J, Sharpe, Ted, Simakov, Oleg, Stadler, Peter F, Stegeman, John J, Sumiyama, Kenta, Tabbaa, Diana, Tafer, Hakim, Turner-Maier, Jason, van Heusden, Peter, White, Simon, Williams, Louise, Yandell, Mark, Brinkmann, Henner, Volff, Jean-Nicolas, Tabin, Clifford J, Shubin, Neil, Schartl, Manfred, Jaffe, David B, Postlethwait, John H, Venkatesh, Byrappa, Di Palma, Frederica, Lander, Eric S, Meyer, Axel, Lindblad-Toh, Kerstin
- Authors: Amemiya, Chris T , Alföldi, Jessica , Lee, Alison P , Fan, Shaohua , Philippe, Herve´ , MacCallum, Iain , Braasch, Ingo , Manousaki, Tereza , Schneider, Igor , Rohner, Nicolas , Organ, Chris , Chalopin, Domitille , Smith, Jeramiah J , Robinson, Mark , Dorrington, Rosemary A , Gerdol, Marco , Aken, Bronwen , Biscotti, Maria Assunta , Barucca, Marco , Baurain, Denis , Berlin, Aaron , Blatch, Gregory L , Buonocore, Francesco , Burmester, Thorsten , Campbell, Michael S , Canapa, Adriana , Cannon, John P , Christoffels, Alan , De Moro, Gianluca , Edkins, Adrienne L , Fan, Lin , Fausto, Anna Maria , Feiner, Nathalie , Forconi, Mariko , Gamieldien, Junaid , Gnerre, Sante , Gnirke, Andreas , Goldstone, Jared V , Haerty, Wilfried , Hahn, Mark E , Hesse, Uljana , Hoffmann, Steve , Johnson, Jeremy , Karchner, Sibel I , Kuraku, Shigehiro , Lara, Marcia , Levin, Joshua Z , Litman, Gary W , Mauceli, Evan , Miyake, Tsutomu , Mueller, M Gail , Nelson, David R , Nitsche, Anne , Olmo, Ettore , Ota, Tatsuya , Pallavicini, Alberto , Panji, Sumir , Picone, Barbara , Ponting, Chris P , Prohaska, Sonja J , Przybylski, Dariusz , Ratan Saha, Nil , Ravi, Vydianathan , Ribeiro, Filipe J , Sauka-Spengler, Tatjana , Scapigliati, Giuseppe , Searle, Stephen M J , Sharpe, Ted , Simakov, Oleg , Stadler, Peter F , Stegeman, John J , Sumiyama, Kenta , Tabbaa, Diana , Tafer, Hakim , Turner-Maier, Jason , van Heusden, Peter , White, Simon , Williams, Louise , Yandell, Mark , Brinkmann, Henner , Volff, Jean-Nicolas , Tabin, Clifford J , Shubin, Neil , Schartl, Manfred , Jaffe, David B , Postlethwait, John H , Venkatesh, Byrappa , Di Palma, Frederica , Lander, Eric S , Meyer, Axel , Lindblad-Toh, Kerstin
- Date: 2013
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165030 , vital:41202 , DOI: 10.1038/nature12027
- Description: The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.
- Full Text:
- Date Issued: 2013
- Authors: Amemiya, Chris T , Alföldi, Jessica , Lee, Alison P , Fan, Shaohua , Philippe, Herve´ , MacCallum, Iain , Braasch, Ingo , Manousaki, Tereza , Schneider, Igor , Rohner, Nicolas , Organ, Chris , Chalopin, Domitille , Smith, Jeramiah J , Robinson, Mark , Dorrington, Rosemary A , Gerdol, Marco , Aken, Bronwen , Biscotti, Maria Assunta , Barucca, Marco , Baurain, Denis , Berlin, Aaron , Blatch, Gregory L , Buonocore, Francesco , Burmester, Thorsten , Campbell, Michael S , Canapa, Adriana , Cannon, John P , Christoffels, Alan , De Moro, Gianluca , Edkins, Adrienne L , Fan, Lin , Fausto, Anna Maria , Feiner, Nathalie , Forconi, Mariko , Gamieldien, Junaid , Gnerre, Sante , Gnirke, Andreas , Goldstone, Jared V , Haerty, Wilfried , Hahn, Mark E , Hesse, Uljana , Hoffmann, Steve , Johnson, Jeremy , Karchner, Sibel I , Kuraku, Shigehiro , Lara, Marcia , Levin, Joshua Z , Litman, Gary W , Mauceli, Evan , Miyake, Tsutomu , Mueller, M Gail , Nelson, David R , Nitsche, Anne , Olmo, Ettore , Ota, Tatsuya , Pallavicini, Alberto , Panji, Sumir , Picone, Barbara , Ponting, Chris P , Prohaska, Sonja J , Przybylski, Dariusz , Ratan Saha, Nil , Ravi, Vydianathan , Ribeiro, Filipe J , Sauka-Spengler, Tatjana , Scapigliati, Giuseppe , Searle, Stephen M J , Sharpe, Ted , Simakov, Oleg , Stadler, Peter F , Stegeman, John J , Sumiyama, Kenta , Tabbaa, Diana , Tafer, Hakim , Turner-Maier, Jason , van Heusden, Peter , White, Simon , Williams, Louise , Yandell, Mark , Brinkmann, Henner , Volff, Jean-Nicolas , Tabin, Clifford J , Shubin, Neil , Schartl, Manfred , Jaffe, David B , Postlethwait, John H , Venkatesh, Byrappa , Di Palma, Frederica , Lander, Eric S , Meyer, Axel , Lindblad-Toh, Kerstin
- Date: 2013
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165030 , vital:41202 , DOI: 10.1038/nature12027
- Description: The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.
- Full Text:
- Date Issued: 2013
The ataxia protein sacsin is a functional co-chaperone that protects against polyglutamine-expanded ataxin-1
- Parfitt, David A, Michael, Gregory J, Vermeulen, Esmeralda G M, Prodromou, Natalia V, Webb, Tom R, Gallo, Jean-Marc, Cheetham, Michael E, Nicoll, William S, Blatch, Gregory L, Chapple, J Paul
- Authors: Parfitt, David A , Michael, Gregory J , Vermeulen, Esmeralda G M , Prodromou, Natalia V , Webb, Tom R , Gallo, Jean-Marc , Cheetham, Michael E , Nicoll, William S , Blatch, Gregory L , Chapple, J Paul
- Date: 2009
- Language: English
- Type: Article
- Identifier: vital:6485 , http://hdl.handle.net/10962/d1006262 , http://hmg.oxfordjournals.org/content/18/9/1556
- Description: An extensive protein–protein interaction network has been identified between proteins implicated in inherited ataxias. The protein sacsin, which is mutated in the early-onset neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix-Saguenay, is a node in this interactome. Here, we have established the neuronal expression of sacsin and functionally characterized domains of the 4579 amino acid protein. Sacsin is most highly expressed in large neurons, particularly within brain motor systems, including cerebellar Purkinje cells. Its subcellular localization in SH-SY5Y neuroblastoma cells was predominantly cytoplasmic with a mitochondrial component. We identified a putative ubiquitin-like (UbL) domain at the N-terminus of sacsin and demonstrated an interaction with the proteasome. Furthermore, sacsin contains a predicted J-domain, the defining feature of DnaJ/Hsp40 proteins. Using a bacterial complementation assay, the sacsin J-domain was demonstrated to be functional. The presence of both UbL and J-domains in sacsin suggests that it may integrate the ubiquitin–proteasome system and Hsp70 function to a specific cellular role. The Hsp70 chaperone machinery is an important component of the cellular response towards aggregation prone mutant proteins that are associated with neurodegenerative diseases. We therefore investigated the effects of siRNA-mediated sacsin knockdown on polyglutamine-expanded ataxin-1. Importantly, SACS siRNA did not affect cell viability with GFP-ataxin-1[30Q], but enhanced the toxicity of GFP-ataxin- 1[82Q], suggesting that sacsin is protective against mutant ataxin-1. Thus, sacsin is an ataxia protein and a regulator of the Hsp70 chaperone machinery that is implicated in the processing of other ataxialinked proteins.
- Full Text:
- Date Issued: 2009
- Authors: Parfitt, David A , Michael, Gregory J , Vermeulen, Esmeralda G M , Prodromou, Natalia V , Webb, Tom R , Gallo, Jean-Marc , Cheetham, Michael E , Nicoll, William S , Blatch, Gregory L , Chapple, J Paul
- Date: 2009
- Language: English
- Type: Article
- Identifier: vital:6485 , http://hdl.handle.net/10962/d1006262 , http://hmg.oxfordjournals.org/content/18/9/1556
- Description: An extensive protein–protein interaction network has been identified between proteins implicated in inherited ataxias. The protein sacsin, which is mutated in the early-onset neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix-Saguenay, is a node in this interactome. Here, we have established the neuronal expression of sacsin and functionally characterized domains of the 4579 amino acid protein. Sacsin is most highly expressed in large neurons, particularly within brain motor systems, including cerebellar Purkinje cells. Its subcellular localization in SH-SY5Y neuroblastoma cells was predominantly cytoplasmic with a mitochondrial component. We identified a putative ubiquitin-like (UbL) domain at the N-terminus of sacsin and demonstrated an interaction with the proteasome. Furthermore, sacsin contains a predicted J-domain, the defining feature of DnaJ/Hsp40 proteins. Using a bacterial complementation assay, the sacsin J-domain was demonstrated to be functional. The presence of both UbL and J-domains in sacsin suggests that it may integrate the ubiquitin–proteasome system and Hsp70 function to a specific cellular role. The Hsp70 chaperone machinery is an important component of the cellular response towards aggregation prone mutant proteins that are associated with neurodegenerative diseases. We therefore investigated the effects of siRNA-mediated sacsin knockdown on polyglutamine-expanded ataxin-1. Importantly, SACS siRNA did not affect cell viability with GFP-ataxin-1[30Q], but enhanced the toxicity of GFP-ataxin- 1[82Q], suggesting that sacsin is protective against mutant ataxin-1. Thus, sacsin is an ataxia protein and a regulator of the Hsp70 chaperone machinery that is implicated in the processing of other ataxialinked proteins.
- Full Text:
- Date Issued: 2009
The complex immunological and inflammatory network of adipose tissue in obesity
- Apostolopoulos, Vasso, De Courten, Maximilian P J, Stojanovska, Lily, Blatch, Gregory L, Tangalakis, Kathy, De Courten, Barbora
- Authors: Apostolopoulos, Vasso , De Courten, Maximilian P J , Stojanovska, Lily , Blatch, Gregory L , Tangalakis, Kathy , De Courten, Barbora
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66120 , vital:28905 , https://doi.org/10.1002/mnfr.201500272
- Description: publisher version , A number of approaches have been utilized in the prevention, management, and treatment of obesity, including, surgery, medication, diet, exercise, and overall lifestyle changes. Despite these interventions, the prevalence of obesity and the various disorders related to it is growing. In obesity, there is a constant state of chronic low‐grade inflammation which is characterized by activation and infiltration of pro‐inflammatory immune cells and a dysregulated production of high levels of pro‐inflammatory cytokines. This pro‐inflammatory milieu contributes to insulin resistance, type‐2 diabetes, cardiovascular disease, and other related co‐morbidities. The roles of the innate (macrophages, neutrophils, eosinophils, mast cells, NK cells, MAIT cells) and the adaptive (CD4 T cells, CD8 T cells, regulatory T cells, and B cells) immune responses and the roles of adipokines and cytokines in adipose tissue inflammation and obesity are discussed. An understanding of the crosstalk between the immune system and adipocytes may shed light in better treatment modalities for obesity and obesity‐related diseases.
- Full Text: false
- Date Issued: 2016
- Authors: Apostolopoulos, Vasso , De Courten, Maximilian P J , Stojanovska, Lily , Blatch, Gregory L , Tangalakis, Kathy , De Courten, Barbora
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66120 , vital:28905 , https://doi.org/10.1002/mnfr.201500272
- Description: publisher version , A number of approaches have been utilized in the prevention, management, and treatment of obesity, including, surgery, medication, diet, exercise, and overall lifestyle changes. Despite these interventions, the prevalence of obesity and the various disorders related to it is growing. In obesity, there is a constant state of chronic low‐grade inflammation which is characterized by activation and infiltration of pro‐inflammatory immune cells and a dysregulated production of high levels of pro‐inflammatory cytokines. This pro‐inflammatory milieu contributes to insulin resistance, type‐2 diabetes, cardiovascular disease, and other related co‐morbidities. The roles of the innate (macrophages, neutrophils, eosinophils, mast cells, NK cells, MAIT cells) and the adaptive (CD4 T cells, CD8 T cells, regulatory T cells, and B cells) immune responses and the roles of adipokines and cytokines in adipose tissue inflammation and obesity are discussed. An understanding of the crosstalk between the immune system and adipocytes may shed light in better treatment modalities for obesity and obesity‐related diseases.
- Full Text: false
- Date Issued: 2016
The Malarial Exported PFA0660w Is an Hsp40 Co-Chaperone of PfHsp70-x
- Daniyan, Michael O, Boshoff, Aileen, Prinsloo, Earl, Pesce, Eva-Rachele, Blatch, Gregory L
- Authors: Daniyan, Michael O , Boshoff, Aileen , Prinsloo, Earl , Pesce, Eva-Rachele , Blatch, Gregory L
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66098 , vital:28901 , https://doi.org/10.1371/journal.pone.0148517
- Description: publisher version , Plasmodium falciparum, the human pathogen responsible for the most dangerous malaria infection, survives and develops in mature erythrocytes through the export of proteins needed for remodelling of the host cell. Molecular chaperones of the heat shock protein (Hsp) family are prominent members of the exportome, including a number of Hsp40s and a Hsp70. PFA0660w, a type II Hsp40, has been shown to be exported and possibly form a complex with PfHsp70-x in the infected erythrocyte cytosol. However, the chaperone properties of PFA0660w and its interaction with human and parasite Hsp70s are yet to be investigated. Recombinant PFA0660w was found to exist as a monomer in solution, and was able to significantly stimulate the ATPase activity of PfHsp70-x but not that of a second plasmodial Hsp70 (PfHsp70-1) or a human Hsp70 (HSPA1A), indicating a potential specific functional partnership with PfHsp70-x. Protein binding studies in the presence and absence of ATP suggested that the interaction of PFA0660w with PfHsp70-x most likely represented a co-chaperone/chaperone interaction. Also, PFA0660w alone produced a concentration-dependent suppression of rhodanese aggregation, demonstrating its chaperone properties. Overall, we have provided the first biochemical evidence for the possible role of PFA0660w as a chaperone and as co-chaperone of PfHsp70-x. We propose that these chaperones boost the chaperone power of the infected erythrocyte, enabling successful protein trafficking and folding, and thereby making a fundamental contribution to the pathology of malaria. , This work was supported by grants from the National Research Foundation (NRF) and Medical Research Council (MRC) of South Africa. The ProteOn XPR36 IAS was purchased from a National Nanotechnology Equipment Programme grant from the Department of Science and Technology and the NRF of South Africa. Michael O. Daniyan was a recipient of the Education Trust Fund (ETF) Academic Staff Training and Development (AST and D) scholarship of Obafemi Awolowo University, Ile-Ife, Nigeria and a Rhodes University Council research bursary
- Full Text:
- Date Issued: 2016
- Authors: Daniyan, Michael O , Boshoff, Aileen , Prinsloo, Earl , Pesce, Eva-Rachele , Blatch, Gregory L
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/66098 , vital:28901 , https://doi.org/10.1371/journal.pone.0148517
- Description: publisher version , Plasmodium falciparum, the human pathogen responsible for the most dangerous malaria infection, survives and develops in mature erythrocytes through the export of proteins needed for remodelling of the host cell. Molecular chaperones of the heat shock protein (Hsp) family are prominent members of the exportome, including a number of Hsp40s and a Hsp70. PFA0660w, a type II Hsp40, has been shown to be exported and possibly form a complex with PfHsp70-x in the infected erythrocyte cytosol. However, the chaperone properties of PFA0660w and its interaction with human and parasite Hsp70s are yet to be investigated. Recombinant PFA0660w was found to exist as a monomer in solution, and was able to significantly stimulate the ATPase activity of PfHsp70-x but not that of a second plasmodial Hsp70 (PfHsp70-1) or a human Hsp70 (HSPA1A), indicating a potential specific functional partnership with PfHsp70-x. Protein binding studies in the presence and absence of ATP suggested that the interaction of PFA0660w with PfHsp70-x most likely represented a co-chaperone/chaperone interaction. Also, PFA0660w alone produced a concentration-dependent suppression of rhodanese aggregation, demonstrating its chaperone properties. Overall, we have provided the first biochemical evidence for the possible role of PFA0660w as a chaperone and as co-chaperone of PfHsp70-x. We propose that these chaperones boost the chaperone power of the infected erythrocyte, enabling successful protein trafficking and folding, and thereby making a fundamental contribution to the pathology of malaria. , This work was supported by grants from the National Research Foundation (NRF) and Medical Research Council (MRC) of South Africa. The ProteOn XPR36 IAS was purchased from a National Nanotechnology Equipment Programme grant from the Department of Science and Technology and the NRF of South Africa. Michael O. Daniyan was a recipient of the Education Trust Fund (ETF) Academic Staff Training and Development (AST and D) scholarship of Obafemi Awolowo University, Ile-Ife, Nigeria and a Rhodes University Council research bursary
- Full Text:
- Date Issued: 2016
The networking of chaperones by co-chaperones: control of cellular protein homeostasis
- Edkins, Adrienne L, Blatch, Gregory L
- Authors: Edkins, Adrienne L , Blatch, Gregory L
- Date: 2014
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/165107 , vital:41209 , ISBN 978-3-319-11731-7
- Description: Co-chaperones are important mediators of the outcome of chaperone assisted protein homeostasis, which is a dynamic balance between the integrated processes of protein folding, degradation and translocation. The Networking of Chaperones by Co-chaperones describes how the function of the major molecular chaperones is regulated by a cohort of diverse non-client proteins, known as co-chaperones. The second edition includes the current status of the field and descriptions of a number of novel co-chaperones that have been recently identified. This new edition has a strong focus on the role of co-chaperones in human disease and as putative drug targets. The book will be a resource for both newcomers and established researchers in the field of cell stress and chaperones, as well as those interested in cross-cutting disciplines such as cellular networks and systems biology.
- Full Text:
- Date Issued: 2014
- Authors: Edkins, Adrienne L , Blatch, Gregory L
- Date: 2014
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/165107 , vital:41209 , ISBN 978-3-319-11731-7
- Description: Co-chaperones are important mediators of the outcome of chaperone assisted protein homeostasis, which is a dynamic balance between the integrated processes of protein folding, degradation and translocation. The Networking of Chaperones by Co-chaperones describes how the function of the major molecular chaperones is regulated by a cohort of diverse non-client proteins, known as co-chaperones. The second edition includes the current status of the field and descriptions of a number of novel co-chaperones that have been recently identified. This new edition has a strong focus on the role of co-chaperones in human disease and as putative drug targets. The book will be a resource for both newcomers and established researchers in the field of cell stress and chaperones, as well as those interested in cross-cutting disciplines such as cellular networks and systems biology.
- Full Text:
- Date Issued: 2014
The PINIT domain of PIAS3: structure-function analysis of its interaction with STAT3
- Mautsa, Nicodemus, Prinsloo, Earl, Tastan Bishop, Özlem, Blatch, Gregory L
- Authors: Mautsa, Nicodemus , Prinsloo, Earl , Tastan Bishop, Özlem , Blatch, Gregory L
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148082 , vital:38708 , DOI: 10.1002/jmr.1111
- Description: The protein inhibitor of activated signal transducer and activator of transcription 3 (PIAS3) regulates the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) which regulates transcription of genes involved in cell growth, proliferation and apoptosis. The conserved proline, isoleucine, asparagine, isoleucine, threonine (PINIT) domain of PIAS3 is thought to promote STAT3–PIAS3 interaction.
- Full Text:
- Date Issued: 2011
- Authors: Mautsa, Nicodemus , Prinsloo, Earl , Tastan Bishop, Özlem , Blatch, Gregory L
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148082 , vital:38708 , DOI: 10.1002/jmr.1111
- Description: The protein inhibitor of activated signal transducer and activator of transcription 3 (PIAS3) regulates the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) which regulates transcription of genes involved in cell growth, proliferation and apoptosis. The conserved proline, isoleucine, asparagine, isoleucine, threonine (PINIT) domain of PIAS3 is thought to promote STAT3–PIAS3 interaction.
- Full Text:
- Date Issued: 2011
The structural and functional diversity of Hsp70 proteins from Plasmodium falciparum
- Shonhai, Addmore, Boshoff, Aileen, Blatch, Gregory L
- Authors: Shonhai, Addmore , Boshoff, Aileen , Blatch, Gregory L
- Date: 2007
- Language: English
- Type: Article
- Identifier: vital:6486 , http://hdl.handle.net/10962/d1006269 , http://dx.doi.org/10.1110/ps.072918107
- Description: It is becoming increasingly apparent that heat shock proteins play an important role in the survival of Plasmodium falciparum against temperature changes associated with its passage from the cold-blooded mosquito vector to the warm-blooded human host. Interest in understanding the possible role of P. falciparum Hsp70s in the life cycle of the parasite has led to the identification of six HSP70 genes. Although most research attention has focused primarily on one of the cytosolic Hsp70s (PfHsp70-1) and its endoplasmic reticulum homolog (PfHsp70-2), further functional insights could be inferred from the structural motifs exhibited by the rest of the Hsp70 family members of P. falciparum. There is increasing evidence that suggests that PfHsp70-1 could play an important role in the life cycle of P. falciparum both as a chaperone and immunogen. In addition, P. falciparum Hsp70s and Hsp40 partners are implicated in the intracellular and extracellular trafficking of proteins. This review summarizes data emerging from studies on the chaperone role of P. falciparum Hsp70s, taking advantage of inferences gleaned from their structures and information on their cellular localization. The possible associations between P. falciparum Hsp70s with their cochaperone partners as well as other chaperones and proteins are discussed.
- Full Text:
- Date Issued: 2007
- Authors: Shonhai, Addmore , Boshoff, Aileen , Blatch, Gregory L
- Date: 2007
- Language: English
- Type: Article
- Identifier: vital:6486 , http://hdl.handle.net/10962/d1006269 , http://dx.doi.org/10.1110/ps.072918107
- Description: It is becoming increasingly apparent that heat shock proteins play an important role in the survival of Plasmodium falciparum against temperature changes associated with its passage from the cold-blooded mosquito vector to the warm-blooded human host. Interest in understanding the possible role of P. falciparum Hsp70s in the life cycle of the parasite has led to the identification of six HSP70 genes. Although most research attention has focused primarily on one of the cytosolic Hsp70s (PfHsp70-1) and its endoplasmic reticulum homolog (PfHsp70-2), further functional insights could be inferred from the structural motifs exhibited by the rest of the Hsp70 family members of P. falciparum. There is increasing evidence that suggests that PfHsp70-1 could play an important role in the life cycle of P. falciparum both as a chaperone and immunogen. In addition, P. falciparum Hsp70s and Hsp40 partners are implicated in the intracellular and extracellular trafficking of proteins. This review summarizes data emerging from studies on the chaperone role of P. falciparum Hsp70s, taking advantage of inferences gleaned from their structures and information on their cellular localization. The possible associations between P. falciparum Hsp70s with their cochaperone partners as well as other chaperones and proteins are discussed.
- Full Text:
- Date Issued: 2007
The TPR2B domain of the Hsp70/Hsp90 organizing protein (Hop) may contribute towards its dimerization
- Longshaw, Victoria M, Stephens, Linda L, Daniel, Sheril, Blatch, Gregory L
- Authors: Longshaw, Victoria M , Stephens, Linda L , Daniel, Sheril , Blatch, Gregory L
- Date: 2009
- Language: English
- Type: Article
- Identifier: vital:6481 , http://hdl.handle.net/10962/d1006253 , http://dx.doi.org/10.2174/092986609787848162
- Description: The role of the TPR2B domain of Hop is as yet unknown. We have shown here by site directed mutagenesis and size exclusion chromatography for the first time that the TPR1 and TPR2B domains of Hop independently dimerized, and that the dimerization of TPR2B was not dependent on its predicted two-carboxylate clamp residues. Furthermore, our data indicated that the dimerization of Hop and its domains was not disrupted in the presence of Hsp70 and Hsp90 peptides.
- Full Text:
- Date Issued: 2009
The TPR2B domain of the Hsp70/Hsp90 organizing protein (Hop) may contribute towards its dimerization
- Authors: Longshaw, Victoria M , Stephens, Linda L , Daniel, Sheril , Blatch, Gregory L
- Date: 2009
- Language: English
- Type: Article
- Identifier: vital:6481 , http://hdl.handle.net/10962/d1006253 , http://dx.doi.org/10.2174/092986609787848162
- Description: The role of the TPR2B domain of Hop is as yet unknown. We have shown here by site directed mutagenesis and size exclusion chromatography for the first time that the TPR1 and TPR2B domains of Hop independently dimerized, and that the dimerization of TPR2B was not dependent on its predicted two-carboxylate clamp residues. Furthermore, our data indicated that the dimerization of Hop and its domains was not disrupted in the presence of Hsp70 and Hsp90 peptides.
- Full Text:
- Date Issued: 2009
Theiler’s murine encephalomyelitis virus infection induces a redistribution of heat shock proteins 70 and 90 in BHK-21 cells, and is inhibited by novobiocin and geldanamycin:
- Mutsvunguma, Lorraine Z, Moetlhoa, Boitumelo, Edkins, Adrienne L, Luke, Garry A, Blatch, Gregory L, Knox, Caroline M
- Authors: Mutsvunguma, Lorraine Z , Moetlhoa, Boitumelo , Edkins, Adrienne L , Luke, Garry A , Blatch, Gregory L , Knox, Caroline M
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165085 , vital:41207 , DOI: 10.1007/s12192-011-0262-x
- Description: Theiler’s murine encephalomyelitis virus (TMEV) is a positive-sense RNA virus belonging to the Cardiovirus genus in the family Picornaviridae. In addition to other host cellular factors and pathways, picornaviruses utilise heat shock proteins (Hsps) to facilitate their propagation in cells. This study investigated the localisation of Hsps 70 and 90 in TMEV-infected BHK-21 cells by indirect immunofluorescence and confocal microscopy. The effect of Hsp90 inhibitors novobiocin (Nov) and geldanamycin (GA) on the development of cytopathic effect (CPE) induced by infection was also examined. Hsp90 staining was uniformly distributed in the cytoplasm of uninfected cells but was found concentrated in the perinuclear region during late infection where it overlapped with the signal for non-structural protein 2C within the viral replication complex.
- Full Text:
- Date Issued: 2011
- Authors: Mutsvunguma, Lorraine Z , Moetlhoa, Boitumelo , Edkins, Adrienne L , Luke, Garry A , Blatch, Gregory L , Knox, Caroline M
- Date: 2011
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165085 , vital:41207 , DOI: 10.1007/s12192-011-0262-x
- Description: Theiler’s murine encephalomyelitis virus (TMEV) is a positive-sense RNA virus belonging to the Cardiovirus genus in the family Picornaviridae. In addition to other host cellular factors and pathways, picornaviruses utilise heat shock proteins (Hsps) to facilitate their propagation in cells. This study investigated the localisation of Hsps 70 and 90 in TMEV-infected BHK-21 cells by indirect immunofluorescence and confocal microscopy. The effect of Hsp90 inhibitors novobiocin (Nov) and geldanamycin (GA) on the development of cytopathic effect (CPE) induced by infection was also examined. Hsp90 staining was uniformly distributed in the cytoplasm of uninfected cells but was found concentrated in the perinuclear region during late infection where it overlapped with the signal for non-structural protein 2C within the viral replication complex.
- Full Text:
- Date Issued: 2011