한빛사 논문
Hyun-Kyoung Kima,*, Geum-Hwa Leea,*, Kashi Raj Bhattaraia, Myung-Shik Leeb, Sung Hoon Backc, Hyung-Ryong Kimd, and Han-Jung Chaea,#
aDepartment of Pharmacology and New Drug Development Research Institute, Chonbuk National University Medical School, Jeonju, Republic of Korea; bSeverance Biomedical Science Institute and Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; cSchool of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea; dCollege of Dentistry, Dankook University, Cheonan, Republic of Korea
*These authors contributed equally to this work
#Corresponding author
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/calcineurinmediated 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.
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