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HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C
Cardiac myosin binding protein C (MYBPC3) is the most commonly mutated gene associated with hypertrophic cardiomyopathy (HCM). Haploinsufficiency of full-length MYBPC3 and disruption of proteostasis have both been proposed as central to HCM disease pathogenesis. Discriminating the relative contribut...
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Published in: | JCI insight 2018-06, Vol.3 (11) |
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creator | Glazier, Amelia A Hafeez, Neha Mellacheruvu, Dattatreya Basrur, Venkatesha Nesvizhskii, Alexey I Lee, Lap Man Shao, Hao Tang, Vi Yob, Jaime M Gestwicki, Jason E Helms, Adam S Day, Sharlene M |
description | Cardiac myosin binding protein C (MYBPC3) is the most commonly mutated gene associated with hypertrophic cardiomyopathy (HCM). Haploinsufficiency of full-length MYBPC3 and disruption of proteostasis have both been proposed as central to HCM disease pathogenesis. Discriminating the relative contributions of these 2 mechanisms requires fundamental knowledge of how turnover of WT and mutant MYBPC3 proteins is regulated. We expressed several disease-causing mutations in MYBPC3 in primary neonatal rat ventricular cardiomyocytes. In contrast to WT MYBPC3, mutant proteins showed reduced expression and failed to localize to the sarcomere. In an unbiased coimmunoprecipitation/mass spectrometry screen, we identified HSP70-family chaperones as interactors of both WT and mutant MYBPC3. Heat shock cognate 70 kDa (HSC70) was the most abundant chaperone interactor. Knockdown of HSC70 significantly slowed degradation of both WT and mutant MYBPC3, while pharmacologic activation of HSC70 and HSP70 accelerated degradation. HSC70 was expressed in discrete striations in the sarcomere. Expression of mutant MYBPC3 did not affect HSC70 localization, nor did it induce a protein folding stress response or ubiquitin proteasome dysfunction. Together these data suggest that WT and mutant MYBPC3 proteins are clients for HSC70, and that the HSC70 chaperone system plays a major role in regulating MYBPC3 protein turnover. |
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Haploinsufficiency of full-length MYBPC3 and disruption of proteostasis have both been proposed as central to HCM disease pathogenesis. Discriminating the relative contributions of these 2 mechanisms requires fundamental knowledge of how turnover of WT and mutant MYBPC3 proteins is regulated. We expressed several disease-causing mutations in MYBPC3 in primary neonatal rat ventricular cardiomyocytes. In contrast to WT MYBPC3, mutant proteins showed reduced expression and failed to localize to the sarcomere. In an unbiased coimmunoprecipitation/mass spectrometry screen, we identified HSP70-family chaperones as interactors of both WT and mutant MYBPC3. Heat shock cognate 70 kDa (HSC70) was the most abundant chaperone interactor. Knockdown of HSC70 significantly slowed degradation of both WT and mutant MYBPC3, while pharmacologic activation of HSC70 and HSP70 accelerated degradation. HSC70 was expressed in discrete striations in the sarcomere. Expression of mutant MYBPC3 did not affect HSC70 localization, nor did it induce a protein folding stress response or ubiquitin proteasome dysfunction. Together these data suggest that WT and mutant MYBPC3 proteins are clients for HSC70, and that the HSC70 chaperone system plays a major role in regulating MYBPC3 protein turnover.</description><identifier>ISSN: 2379-3708</identifier><identifier>EISSN: 2379-3708</identifier><identifier>DOI: 10.1172/jci.insight.99319</identifier><identifier>PMID: 29875314</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Acetylcysteine - analogs & derivatives ; Acetylcysteine - pharmacology ; Animals ; Animals, Newborn ; Cardiomyopathy, Hypertrophic - genetics ; Cardiomyopathy, Hypertrophic - pathology ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Cell Nucleus - metabolism ; Gene Knockdown Techniques ; Haploinsufficiency ; HEK293 Cells ; HSC70 Heat-Shock Proteins - genetics ; HSC70 Heat-Shock Proteins - metabolism ; Humans ; Myocardium - pathology ; Proteasome Endopeptidase Complex - drug effects ; Proteasome Inhibitors - pharmacology ; Proteolysis - drug effects ; Proteostasis - genetics ; Rats ; Sarcomeres - pathology ; Ventricular Septum - pathology</subject><ispartof>JCI insight, 2018-06, Vol.3 (11)</ispartof><rights>Copyright © 2018, American Society for Clinical Investigation 2018 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c465t-f828a498bd7b656412eee8cc74ae0e30735fddbd90ef902b603c0c580f8a48e93</citedby><cites>FETCH-LOGICAL-c465t-f828a498bd7b656412eee8cc74ae0e30735fddbd90ef902b603c0c580f8a48e93</cites><orcidid>0000-0003-2506-4329 ; 0000-0001-6079-9756 ; 0000-0001-8221-7673</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124431/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124431/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29875314$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Glazier, Amelia A</creatorcontrib><creatorcontrib>Hafeez, Neha</creatorcontrib><creatorcontrib>Mellacheruvu, Dattatreya</creatorcontrib><creatorcontrib>Basrur, Venkatesha</creatorcontrib><creatorcontrib>Nesvizhskii, Alexey I</creatorcontrib><creatorcontrib>Lee, Lap Man</creatorcontrib><creatorcontrib>Shao, Hao</creatorcontrib><creatorcontrib>Tang, Vi</creatorcontrib><creatorcontrib>Yob, Jaime M</creatorcontrib><creatorcontrib>Gestwicki, Jason E</creatorcontrib><creatorcontrib>Helms, Adam S</creatorcontrib><creatorcontrib>Day, Sharlene M</creatorcontrib><title>HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C</title><title>JCI insight</title><addtitle>JCI Insight</addtitle><description>Cardiac myosin binding protein C (MYBPC3) is the most commonly mutated gene associated with hypertrophic cardiomyopathy (HCM). Haploinsufficiency of full-length MYBPC3 and disruption of proteostasis have both been proposed as central to HCM disease pathogenesis. Discriminating the relative contributions of these 2 mechanisms requires fundamental knowledge of how turnover of WT and mutant MYBPC3 proteins is regulated. We expressed several disease-causing mutations in MYBPC3 in primary neonatal rat ventricular cardiomyocytes. In contrast to WT MYBPC3, mutant proteins showed reduced expression and failed to localize to the sarcomere. In an unbiased coimmunoprecipitation/mass spectrometry screen, we identified HSP70-family chaperones as interactors of both WT and mutant MYBPC3. Heat shock cognate 70 kDa (HSC70) was the most abundant chaperone interactor. Knockdown of HSC70 significantly slowed degradation of both WT and mutant MYBPC3, while pharmacologic activation of HSC70 and HSP70 accelerated degradation. HSC70 was expressed in discrete striations in the sarcomere. Expression of mutant MYBPC3 did not affect HSC70 localization, nor did it induce a protein folding stress response or ubiquitin proteasome dysfunction. Together these data suggest that WT and mutant MYBPC3 proteins are clients for HSC70, and that the HSC70 chaperone system plays a major role in regulating MYBPC3 protein turnover.</description><subject>Acetylcysteine - analogs & derivatives</subject><subject>Acetylcysteine - pharmacology</subject><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Cardiomyopathy, Hypertrophic - genetics</subject><subject>Cardiomyopathy, Hypertrophic - pathology</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell Nucleus - metabolism</subject><subject>Gene Knockdown Techniques</subject><subject>Haploinsufficiency</subject><subject>HEK293 Cells</subject><subject>HSC70 Heat-Shock Proteins - genetics</subject><subject>HSC70 Heat-Shock Proteins - metabolism</subject><subject>Humans</subject><subject>Myocardium - pathology</subject><subject>Proteasome Endopeptidase Complex - drug effects</subject><subject>Proteasome Inhibitors - pharmacology</subject><subject>Proteolysis - drug effects</subject><subject>Proteostasis - genetics</subject><subject>Rats</subject><subject>Sarcomeres - pathology</subject><subject>Ventricular Septum - pathology</subject><issn>2379-3708</issn><issn>2379-3708</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNpVUU1LxDAQDaKoqD_Ai-TopWs-2ia5CLL4BaIH9RzSZLobaZOadJX991ZdRU8zw7z3ZngPoWNKZpQKdvZi_cyH7BfLcaYUp2oL7TMuVMEFkdt_-j10lPMLIYSKkpFK7qI9pqSoOC330f3N41wQ7DM22C7NACkGwG1M-N13rhjXA2ATHO5XowkjtiY5byzu1zH7gBsfnA8LPKQ4wjTPD9FOa7oMR5t6gJ6vLp_mN8Xdw_Xt_OKusGVdjUUrmTSlko0TTV3VJWUAIK0VpQECnAhetc41ThFoFWFNTbgltpKknWgSFD9A59-6w6rpwVkIYzKdHpLvTVrraLz-vwl-qRfxTdeUlSWnk8DpRiDF1xXkUfc-W-g6EyCusp6MonVNhWQTlH5DbYo5J2h_z1CiP6PQUxR6E4X-imLinPz975fxYzz_AEWIiGA</recordid><startdate>20180607</startdate><enddate>20180607</enddate><creator>Glazier, Amelia A</creator><creator>Hafeez, Neha</creator><creator>Mellacheruvu, Dattatreya</creator><creator>Basrur, Venkatesha</creator><creator>Nesvizhskii, Alexey I</creator><creator>Lee, Lap Man</creator><creator>Shao, Hao</creator><creator>Tang, Vi</creator><creator>Yob, Jaime M</creator><creator>Gestwicki, Jason E</creator><creator>Helms, Adam S</creator><creator>Day, Sharlene M</creator><general>American Society for Clinical Investigation</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2506-4329</orcidid><orcidid>https://orcid.org/0000-0001-6079-9756</orcidid><orcidid>https://orcid.org/0000-0001-8221-7673</orcidid></search><sort><creationdate>20180607</creationdate><title>HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C</title><author>Glazier, Amelia A ; Hafeez, Neha ; Mellacheruvu, Dattatreya ; Basrur, Venkatesha ; Nesvizhskii, Alexey I ; Lee, Lap Man ; Shao, Hao ; Tang, Vi ; Yob, Jaime M ; Gestwicki, Jason E ; Helms, Adam S ; Day, Sharlene M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c465t-f828a498bd7b656412eee8cc74ae0e30735fddbd90ef902b603c0c580f8a48e93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Acetylcysteine - analogs & derivatives</topic><topic>Acetylcysteine - pharmacology</topic><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Cardiomyopathy, Hypertrophic - genetics</topic><topic>Cardiomyopathy, Hypertrophic - pathology</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>Cell Nucleus - metabolism</topic><topic>Gene Knockdown Techniques</topic><topic>Haploinsufficiency</topic><topic>HEK293 Cells</topic><topic>HSC70 Heat-Shock Proteins - genetics</topic><topic>HSC70 Heat-Shock Proteins - metabolism</topic><topic>Humans</topic><topic>Myocardium - pathology</topic><topic>Proteasome Endopeptidase Complex - drug effects</topic><topic>Proteasome Inhibitors - pharmacology</topic><topic>Proteolysis - drug effects</topic><topic>Proteostasis - genetics</topic><topic>Rats</topic><topic>Sarcomeres - pathology</topic><topic>Ventricular Septum - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Glazier, Amelia A</creatorcontrib><creatorcontrib>Hafeez, Neha</creatorcontrib><creatorcontrib>Mellacheruvu, Dattatreya</creatorcontrib><creatorcontrib>Basrur, Venkatesha</creatorcontrib><creatorcontrib>Nesvizhskii, Alexey I</creatorcontrib><creatorcontrib>Lee, Lap Man</creatorcontrib><creatorcontrib>Shao, Hao</creatorcontrib><creatorcontrib>Tang, Vi</creatorcontrib><creatorcontrib>Yob, Jaime M</creatorcontrib><creatorcontrib>Gestwicki, Jason E</creatorcontrib><creatorcontrib>Helms, Adam S</creatorcontrib><creatorcontrib>Day, Sharlene M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>JCI insight</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Glazier, Amelia A</au><au>Hafeez, Neha</au><au>Mellacheruvu, Dattatreya</au><au>Basrur, Venkatesha</au><au>Nesvizhskii, Alexey I</au><au>Lee, Lap Man</au><au>Shao, Hao</au><au>Tang, Vi</au><au>Yob, Jaime M</au><au>Gestwicki, Jason E</au><au>Helms, Adam S</au><au>Day, Sharlene M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C</atitle><jtitle>JCI insight</jtitle><addtitle>JCI Insight</addtitle><date>2018-06-07</date><risdate>2018</risdate><volume>3</volume><issue>11</issue><issn>2379-3708</issn><eissn>2379-3708</eissn><abstract>Cardiac myosin binding protein C (MYBPC3) is the most commonly mutated gene associated with hypertrophic cardiomyopathy (HCM). Haploinsufficiency of full-length MYBPC3 and disruption of proteostasis have both been proposed as central to HCM disease pathogenesis. Discriminating the relative contributions of these 2 mechanisms requires fundamental knowledge of how turnover of WT and mutant MYBPC3 proteins is regulated. We expressed several disease-causing mutations in MYBPC3 in primary neonatal rat ventricular cardiomyocytes. In contrast to WT MYBPC3, mutant proteins showed reduced expression and failed to localize to the sarcomere. In an unbiased coimmunoprecipitation/mass spectrometry screen, we identified HSP70-family chaperones as interactors of both WT and mutant MYBPC3. Heat shock cognate 70 kDa (HSC70) was the most abundant chaperone interactor. Knockdown of HSC70 significantly slowed degradation of both WT and mutant MYBPC3, while pharmacologic activation of HSC70 and HSP70 accelerated degradation. HSC70 was expressed in discrete striations in the sarcomere. Expression of mutant MYBPC3 did not affect HSC70 localization, nor did it induce a protein folding stress response or ubiquitin proteasome dysfunction. Together these data suggest that WT and mutant MYBPC3 proteins are clients for HSC70, and that the HSC70 chaperone system plays a major role in regulating MYBPC3 protein turnover.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>29875314</pmid><doi>10.1172/jci.insight.99319</doi><orcidid>https://orcid.org/0000-0003-2506-4329</orcidid><orcidid>https://orcid.org/0000-0001-6079-9756</orcidid><orcidid>https://orcid.org/0000-0001-8221-7673</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Acetylcysteine - analogs & derivatives Acetylcysteine - pharmacology Animals Animals, Newborn Cardiomyopathy, Hypertrophic - genetics Cardiomyopathy, Hypertrophic - pathology Carrier Proteins - genetics Carrier Proteins - metabolism Cell Nucleus - metabolism Gene Knockdown Techniques Haploinsufficiency HEK293 Cells HSC70 Heat-Shock Proteins - genetics HSC70 Heat-Shock Proteins - metabolism Humans Myocardium - pathology Proteasome Endopeptidase Complex - drug effects Proteasome Inhibitors - pharmacology Proteolysis - drug effects Proteostasis - genetics Rats Sarcomeres - pathology Ventricular Septum - pathology |
title | HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C |
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