Page 2 - F. Cell biology

[F. Cell biology-1]

TMBIM6 (transmembrane BAX inhibitor motif containing 6)

enhances autophagy through regulation of lysosomal calcium

Hyun-Kyoung Kim¹, Hyung-Ryong Kim⁴, Geum-Hwa Lee¹, Kashi Raj Bhattarai¹, Myung-Shik Lee²,

Sung Hoon Back³, Han-Jung Chae¹

¹Department of Pharmacology and New Drug Development Research Institute, Chonbuk National University
Medical School, Jeonju 54896, Republic of Korea, ²Severance Biomedical Science Institute and Department of

Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea, ³School of Biological

Sciences, University of Ulsan, Ulsan 44610, Republic of Korea, ⁴College of Dentistry, Dankook University, Cheonan
31116, Republic of Korea

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. Together, our observations indicated
that under stress conditions, TMBIM6 increases lysosomal Ca2+ release, leading to PPP3/calcineurinmediated TFEB
activation and subsequently enhanced autophagy.