They dephosphorylate phosphatidylinositol-3-phosphate (PtdIns3P) and phosphatidylinositol-3,5-bisphosphate (PtdIns P 2) at the D3 position to generate phosphatidylinositol (PtdIns) and phosphatidylinositol-5-phosphate (PtdIns5P), respectively ( Figure 1B). Out of the sixteen mammalian MTM/MTMR paralogs (MTM and MTMR1-MTMR15), nine have catalytic activity ( Figure 1A). Myotubularin (MTM) and myotubularin-related (MTMR) phosphatases share a Cys-X5-Ar g motif, and their catalytic activity is specific to phosphoinositides, which are important components of lipid membranes. These results provide a deeper insight into the adjustment of autophagy.Ībbreviations: Atg, autophagy-related BDSC, Bloomington Drosophila Stock Center DGRC, Drosophila Genetic Resource Center EDTP, Egg-derived tyrosine phosphatase FYVE, zinc finger domain from Fab1 (yeast ortholog of PIKfyve), YOTB, Vac1 (vesicle transport protein) and EEA1 cysteine-rich proteins LTR, LysoTracker Red MTM, myotubularin MTMR, myotubularin-related PI, phosphatidylinositol Pi3K59F, Phosphotidylinositol 3 kinase 59F PtdIns3P, phosphatidylinositol-3-phosphate PtdIns(3,5)P 2, phosphatidylinositol-3,5-bisphosphate PtdIns5P, phosphatidylinositol-5-phosphate ref(2)P, refractory to sigma P Syx17, Syntaxin 17 TEM, transmission electron microscopy UAS, upstream activating sequence Uvrag, UV-resistance associated gene VDRC, Vienna Drosophila RNAi Center Vps34, Vacuolar protein sorting 34. Thus, Mtmr6 is the first identified MTMR phosphatase with dual, antagonistic roles in the regulation of autophagy, and shows conditional antagonism/synergism with EDTP in modulating autophagic breakdown. In contrast, Mtmr6 promoted the process under nutrient-rich settings, but effectively blocked its hyperactivation in response to stress. EDTP inhibited basal autophagy, but did not influence stress-induced autophagy. Here we examined two Drosophila MTMRs, EDTP and Mtmr6, the fly orthologs of mammalian MTMR14 and MTMR6 to MTMR8, respectively, and found that these enzymes affect the autophagic process in a complex, condition-dependent way. Despite its physiological and medical significance, the specific role of individual MTMR paralogs in autophagy control remains largely unexplored. Because some of these substrates are required for macroautophagy/autophagy, during which unwanted cytoplasmic constituents are delivered into lysosomes for degradation, MTM and MTMRs function as important regulators of the autophagic process. Myotubularin (MTM) and myotubularin-related (MTMR) lipid phosphatases catalyze the removal of a phosphate group from certain phosphatidylinositol derivatives.
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