Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
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Gene/Protein
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Target Concepts:
Gene/Protein
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Query: UMLS:C0038187 (
starvation
)
24,951
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Lysosomal Ca
2+
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 Ca
2+
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 Ca
2+
levels. The Ca
2+
efflux from the ER through
TMBIM6
was found to increase the resting lysosomal Ca
2+
level, in which ITPR-independent regulation of Ca
2+
status was observed. Further,
TMBIM6
regulated the local release of Ca
2+
through lysosomal MCOLN1/TRPML1 channels under nutrient
starvation
or MTOR inhibition. The local Ca
2+
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 Ca
2+
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 Ca
2+
release, leading to PPP3/calcineurin-mediated TFEB activation and subsequently enhanced autophagy. Thus,
TMBIM6
, an ER membrane protein, is suggested to be a lysosomal Ca
2+
modulator that coordinates with autophagy to alleviate metabolism stress.
Abbreviations
: AVs: autophagic vacuoles; CEPIA: calcium-measuring organelle-entrapped protein indicator; ER: endoplasmic reticulum; GPN: glycyl-L-phenylalanine-beta-naphthylamide; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; LAMP1: lysosomal associated membrane protein 1; MCOLN/TRPML: mucolipin; MEF: mouse embryonic fibroblast; ML-SA1: mucolipin synthetic agonist 1; MTORC1: mechanistic target of rapamycin kinase complex 1; RPS6KB1: ribosomal protein S6 kinase B1; SQSTM1: sequestosome 1; TFEB: transcription factor EB; TKO: triple knockout;
TMBIM6
/BI-1: transmembrane BAX inhibitor motif containing 6.
...
PMID:TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy through regulation of lysosomal calcium. 3216 7
