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The lysosomal Ca2+ release channel TRPML1 regulates lysosome size by activating calmodulin
Intracellular lysosomal membrane trafficking, including fusion and fission, is crucial for cellular homeostasis and normal cell function. Both fusion and fission of lysosomal membrane are accompanied by lysosomal Ca2+ release. We recently have demonstrated that the lysosomal Ca2+ release channel P2X...
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Published in: | The Journal of biological chemistry 2017-05, Vol.292 (20), p.8424-8435 |
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description | Intracellular lysosomal membrane trafficking, including fusion and fission, is crucial for cellular homeostasis and normal cell function. Both fusion and fission of lysosomal membrane are accompanied by lysosomal Ca2+ release. We recently have demonstrated that the lysosomal Ca2+ release channel P2X4 regulates lysosome fusion through a calmodulin (CaM)-dependent mechanism. However, the molecular mechanism underlying lysosome fission remains uncertain. In this study, we report that enlarged lysosomes/vacuoles induced by either vacuolin-1 or P2X4 activation are suppressed by up-regulating the lysosomal Ca2+ release channel transient receptor potential mucolipin 1 (TRPML1) but not the lysosomal Na+ release channel two-pore channel 2 (TPC2). Activation of TRPML1 facilitated the recovery of enlarged lysosomes/vacuoles. Moreover, the effects of TRPML1 on lysosome/vacuole size regulation were eliminated by Ca2+ chelation, suggesting a requirement for TRPML1-mediated Ca2+ release. We further demonstrate that the prototypical Ca2+ sensor CaM is required for the regulation of lysosome/vacuole size by TRPML1, suggesting that TRPML1 may promote lysosome fission by activating CaM. Given that lysosome fission is implicated in both lysosome biogenesis and reformation, our findings suggest that TRPML1 may function as a key lysosomal Ca2+ channel controlling both lysosome biogenesis and reformation. |
doi_str_mv | 10.1074/jbc.M116.772160 |
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Both fusion and fission of lysosomal membrane are accompanied by lysosomal Ca2+ release. We recently have demonstrated that the lysosomal Ca2+ release channel P2X4 regulates lysosome fusion through a calmodulin (CaM)-dependent mechanism. However, the molecular mechanism underlying lysosome fission remains uncertain. In this study, we report that enlarged lysosomes/vacuoles induced by either vacuolin-1 or P2X4 activation are suppressed by up-regulating the lysosomal Ca2+ release channel transient receptor potential mucolipin 1 (TRPML1) but not the lysosomal Na+ release channel two-pore channel 2 (TPC2). Activation of TRPML1 facilitated the recovery of enlarged lysosomes/vacuoles. Moreover, the effects of TRPML1 on lysosome/vacuole size regulation were eliminated by Ca2+ chelation, suggesting a requirement for TRPML1-mediated Ca2+ release. We further demonstrate that the prototypical Ca2+ sensor CaM is required for the regulation of lysosome/vacuole size by TRPML1, suggesting that TRPML1 may promote lysosome fission by activating CaM. Given that lysosome fission is implicated in both lysosome biogenesis and reformation, our findings suggest that TRPML1 may function as a key lysosomal Ca2+ channel controlling both lysosome biogenesis and reformation.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M116.772160</identifier><identifier>PMID: 28360104</identifier><language>eng</language><publisher>11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A: Elsevier Inc</publisher><subject>calcium ; calcium channel ; calmodulin (CaM) ; Cell Biology ; lysosomal Ca2 ; lysosome ; membrane trafficking ; trpml1</subject><ispartof>The Journal of biological chemistry, 2017-05, Vol.292 (20), p.8424-8435</ispartof><rights>2017 © 2017 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology</rights><rights>2017 by The American Society for Biochemistry and Molecular Biology, Inc. 2017 The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c416t-5ac6727c5f027f19d9d2a98e3cab3aa557a8787aef07480718730d33701097ce3</citedby><cites>FETCH-LOGICAL-c416t-5ac6727c5f027f19d9d2a98e3cab3aa557a8787aef07480718730d33701097ce3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437247/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0021925820394217$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,3549,27924,27925,45780,53791,53793</link.rule.ids></links><search><creatorcontrib>Cao, Qi</creatorcontrib><creatorcontrib>Yang, Yiming</creatorcontrib><creatorcontrib>Zhong, Xi Zoë</creatorcontrib><creatorcontrib>Dong, Xian-Ping</creatorcontrib><title>The lysosomal Ca2+ release channel TRPML1 regulates lysosome size by activating calmodulin</title><title>The Journal of biological chemistry</title><description>Intracellular lysosomal membrane trafficking, including fusion and fission, is crucial for cellular homeostasis and normal cell function. Both fusion and fission of lysosomal membrane are accompanied by lysosomal Ca2+ release. We recently have demonstrated that the lysosomal Ca2+ release channel P2X4 regulates lysosome fusion through a calmodulin (CaM)-dependent mechanism. However, the molecular mechanism underlying lysosome fission remains uncertain. In this study, we report that enlarged lysosomes/vacuoles induced by either vacuolin-1 or P2X4 activation are suppressed by up-regulating the lysosomal Ca2+ release channel transient receptor potential mucolipin 1 (TRPML1) but not the lysosomal Na+ release channel two-pore channel 2 (TPC2). Activation of TRPML1 facilitated the recovery of enlarged lysosomes/vacuoles. Moreover, the effects of TRPML1 on lysosome/vacuole size regulation were eliminated by Ca2+ chelation, suggesting a requirement for TRPML1-mediated Ca2+ release. We further demonstrate that the prototypical Ca2+ sensor CaM is required for the regulation of lysosome/vacuole size by TRPML1, suggesting that TRPML1 may promote lysosome fission by activating CaM. Given that lysosome fission is implicated in both lysosome biogenesis and reformation, our findings suggest that TRPML1 may function as a key lysosomal Ca2+ channel controlling both lysosome biogenesis and reformation.</description><subject>calcium</subject><subject>calcium channel</subject><subject>calmodulin (CaM)</subject><subject>Cell Biology</subject><subject>lysosomal Ca2</subject><subject>lysosome</subject><subject>membrane trafficking</subject><subject>trpml1</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNp1UUtrGzEQFqEhcdOee9UxUNbRY3elvRSKadOAQ0JxofQixtpZW0G7SqVdg_PrI-Mk0EPnMjDzPZj5CPnE2ZwzVV49rO38lvN6rpTgNTshM860LGTFf78jM8YELxpR6XPyPqUHlqts-Bk5F1rWjLNyRv6stkj9PoUUevB0AeIzjegRElK7hWFAT1c_72-XPI83k4cR0yseaXJPSNd7CnZ0OxjdsKEWfB_aybvhAzntwCf8-NIvyK_v31aLH8Xy7vpm8XVZ2JLXY1GBrZVQtuqYUB1v2qYV0GiUFtYSoKoUaKUVYJcP1kxxrSRrpVT5gEZZlBfky1H3cVr32FocxgjePEbXQ9ybAM78uxnc1mzCzlSlVKJUWeDyRSCGvxOm0fQuWfQeBgxTMlxryfXBLkOvjlAbQ0oRuzcbzswhEZMTMYdEzDGRzGiODMwv2DmMJlmHg8XWRbSjaYP7L_cZ-CmRUA</recordid><startdate>201705</startdate><enddate>201705</enddate><creator>Cao, Qi</creator><creator>Yang, Yiming</creator><creator>Zhong, Xi Zoë</creator><creator>Dong, Xian-Ping</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201705</creationdate><title>The lysosomal Ca2+ release channel TRPML1 regulates lysosome size by activating calmodulin</title><author>Cao, Qi ; Yang, Yiming ; Zhong, Xi Zoë ; Dong, Xian-Ping</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c416t-5ac6727c5f027f19d9d2a98e3cab3aa557a8787aef07480718730d33701097ce3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>calcium</topic><topic>calcium channel</topic><topic>calmodulin (CaM)</topic><topic>Cell Biology</topic><topic>lysosomal Ca2</topic><topic>lysosome</topic><topic>membrane trafficking</topic><topic>trpml1</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cao, Qi</creatorcontrib><creatorcontrib>Yang, Yiming</creatorcontrib><creatorcontrib>Zhong, Xi Zoë</creatorcontrib><creatorcontrib>Dong, Xian-Ping</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cao, Qi</au><au>Yang, Yiming</au><au>Zhong, Xi Zoë</au><au>Dong, Xian-Ping</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The lysosomal Ca2+ release channel TRPML1 regulates lysosome size by activating calmodulin</atitle><jtitle>The Journal of biological chemistry</jtitle><date>2017-05</date><risdate>2017</risdate><volume>292</volume><issue>20</issue><spage>8424</spage><epage>8435</epage><pages>8424-8435</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Intracellular lysosomal membrane trafficking, including fusion and fission, is crucial for cellular homeostasis and normal cell function. Both fusion and fission of lysosomal membrane are accompanied by lysosomal Ca2+ release. We recently have demonstrated that the lysosomal Ca2+ release channel P2X4 regulates lysosome fusion through a calmodulin (CaM)-dependent mechanism. However, the molecular mechanism underlying lysosome fission remains uncertain. In this study, we report that enlarged lysosomes/vacuoles induced by either vacuolin-1 or P2X4 activation are suppressed by up-regulating the lysosomal Ca2+ release channel transient receptor potential mucolipin 1 (TRPML1) but not the lysosomal Na+ release channel two-pore channel 2 (TPC2). Activation of TRPML1 facilitated the recovery of enlarged lysosomes/vacuoles. Moreover, the effects of TRPML1 on lysosome/vacuole size regulation were eliminated by Ca2+ chelation, suggesting a requirement for TRPML1-mediated Ca2+ release. 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subjects | calcium calcium channel calmodulin (CaM) Cell Biology lysosomal Ca2 lysosome membrane trafficking trpml1 |
title | The lysosomal Ca2+ release channel TRPML1 regulates lysosome size by activating calmodulin |
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