期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 292, 期 20, 页码 8424-8435出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.772160
关键词
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资金
- Department of Physiology and Biophysics
- Dalhousie University
- Dalhousie Medical Research Foundation (DMRF) Equipment Grant
- DMRF new investigator award
- Canadian Institutes of Health Research Grant [MOP-119349]
- Canadian Institutes of Health Research New Investigator Award [201109MSH261462-208625]
- Nova Scotia Health Research Foundation (NSHRF) Establishment Grant [MED-PRO-2011-7485]
- Canada Foundation for Innovation (CFI) Leaders Opportunity Fund for Research Infrastructure Grant [29291]
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.
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