期刊
BIOCHEMICAL JOURNAL
卷 470, 期 -, 页码 331-342出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20150219
关键词
adenosine 5 '-phosphate (AMP)-activated protein kinase; autophagy; lysosomal storage disease; mammalian target of rapamycin; mucolipidosis type IV; transient receptor potential channels
资金
- state of North Carolina (University Cancer Research Fund)
- National Institute of Health [1-DP2-0D007149-01, NS080108]
Autophagy is a complex pathway regulated by numerous signalling events that recycles macromolecules and may be perturbed in lysosomal storage disorders (LSDs). During autophagy, aberrant regulation of the lysosomal Ca2+ efflux channel TRPML1 [transient receptor potential mucolipin 1 (MCOLN1)], also known as MCOLN1, is solely responsible for the human LSD mucolipidosis type IV (MLIV); however, the exact mechanisms involved in the development of the pathology of this LSD are unknown. In the present study, we provide evidence that the target of rapamycin (TOR), a nutrient-sensitive protein kinase that negatively regulates autophagy, directly targets and inactivates the TRPML1 channel and thereby functional autophagy, through phosphorylation. Further, mutating these phosphorylation sites to unphosphorylatable residues proved to block TOR regulation of the TRPML1 channel. These findings suggest a mechanism for how TOR activity may regulate the TRPML1 channel.
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