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TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy through regulation of lysosomal calcium

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Alternative Title
TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy through regulation of lysosomal calcium
Abstract
Lysosomal Ca2+ contributes to macroautophagy/autophagy, an intracellular process for the degradation of cytoplasmic material and organelles in the lysosomes to protect cells against stress responses. TMBIM6 (transmembrane BAX inhibitor motif containing 6) is a Ca2+ channel-like protein known to regulate ER stress response and apoptosis. In this study, we examined the as yet unknown role of TMBIM6 in regulating lysosomal Ca2+ levels. The Ca2+ efflux from the ER through TMBIM6 was found to increase the resting lysosomal Ca2+ level, in which ITPR-independent regulation of Ca2+ status was observed. Further, TMBIM6 regulated the local release of Ca2+ through lysosomal MCOLN1/TRPML1 channels under nutrient starvation or MTOR inhibition. The local Ca2+ efflux through MCOLN1 channels was found to activate PPP3/calcineurin, triggering TFEB (transcription factor EB) nuclear translocation, autophagy induction, and lysosome biogenesis. Upon genetic inactivation of TMBIM6, lysosomal Ca2+ and the associated TFEB nuclear translocation were decreased. Furthermore, autophagy flux was significantly enhanced in the liver or kidney from starved Tmbim6+/+ mice compared with that in the counter tmbim6-/- mice. Together, our observations indicated that under stress conditions, TMBIM6 increases lysosomal Ca2+ release, leading to PPP3/calcineurin-mediated TFEB activation and subsequently enhanced autophagy. Thus, TMBIM6, an ER membrane protein, is suggested to be a lysosomal Ca2+ modulator that coordinates with autophagy to alleviate metabolism stress.
Author(s)
Hyun-Kyoung KimGeum-Hwa LeeKashi Raj BhattaraiMyung-Shik Lee백승훈Hyung-Ryong KimdHan-Jung Chae
Issued Date
2021
Type
Article
Keyword
Autophagylysosomal calciumMTORC1Research PaperTMBIM6transcription factor EB (TFEB)
DOI
10.1080/15548627.2020.1732161
URI
https://oak.ulsan.ac.kr/handle/2021.oak/9565
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_proquest_miscellaneous_2377342962&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,TMBIM6%20(transmembrane%20BAX%20inhibitor%20motif%20containing%206)%20enhances%20autophagy%20through%20regulation%20of%20lysosomal%20calcium&offset=0&pcAvailability=true
Publisher
Autophagy
Location
미국
Language
영어
ISSN
1554-8627
Citation Volume
17
Citation Number
3
Citation Start Page
761
Citation End Page
778
Appears in Collections:
Natural Science > Biological Sciences
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