The mucolipidosis IV Ca2+ channel TRPML1 (MCOLN1) is regulated by the TOR kinase
| Autor: | Jonathan Z. Sexton, Michael B. Major, Jay E. Brenman, Rob U. Onyenwoke, Feng Yan, Lawrence J. Forsberg, María Cristina Huertas Díaz |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
mucolipidosis type IV
Male autophagy Recombinant Fusion Proteins Molecular Sequence Data Genes Insect Biology AMP-Activated Protein Kinases Biochemistry Models Biological Animals Genetically Modified Transient Receptor Potential Channels Mucolipidoses medicine Animals Drosophila Proteins Humans Amino Acid Sequence Calcium Signaling Phosphorylation Protein kinase A Molecular Biology Research Articles mammalian target of rapamycin Binding Sites Mucolipidosis Kinase TOR Serine-Threonine Kinases Autophagy Cell Biology Autophagy-related protein 13 medicine.disease Drosophila melanogaster HEK293 Cells lysosomal storage disease adenosine 5′-phosphate (AMP)-activated protein kinase Gene Knockdown Techniques Mutagenesis Site-Directed Female RNA Interference Mucolipidosis type IV Research Article |
| Zdroj: | Biochemical Journal |
| ISSN: | 1470-8728 0264-6021 |
| Popis: | The exact mechanisms underlying the lysosomal storage disorder (LSD) mucolipidosis type IV (MLIV) are unclear. In the present study, we provide evidence that mTOR regulates the opening and closing of the lysosomal channel responsible for MLIV through phosphorylation. 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. |
| Databáze: | OpenAIRE |
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