title: The mucolipidosis IV Ca2+ channel TRPML1 (MCOLN1) is regulated by the TOR kinase.
abstract: 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 Ca(2+) 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.
authors.affiliation: Biomanufacturing Research Institute and Technology Enterprise (BRITE), North Carolina Central University, Durham, NC 27707, U.S.A. ronyenwo@nccu.edu).
authors.forename: Rob U
authors.initials: RU
authors.lastname: Onyenwoke
authors.affiliation: Biomanufacturing Research Institute and Technology Enterprise (BRITE), North Carolina Central University, Durham, NC 27707, U.S.A.
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Sexton
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.affiliation: Neuroscience Center, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: María Cristina Huertas
authors.initials: MC
authors.lastname: Díaz
authors.affiliation: Neuroscience Center, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Forsberg
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Major
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, U.S.A. Neuroscience Center, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, U.S.A.
authors.forename: Jay E
authors.initials: JE
authors.lastname: Brenman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy; D001665:Binding Sites; D020013:Calcium Signaling; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D017344:Genes, Insect; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D009081:Mucolipidoses / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; C416674:MCOLN1 protein, human; D011993:Recombinant Fusion Proteins; D050051:Transient Receptor Potential Channels; C546842:MTOR protein, human; C523914:AMPKalpha protein, Drosophila; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: adenosine 5′-phosphate (AMP)-activated protein kinase; autophagy; lysosomal storage disease; mammalian target of rapamycin; mucolipidosis type IV; transient receptor potential channels