title: Drosophila TRPML is required for TORC1 activation.
abstract: Loss-of-function mutations in TRPML1 (transient receptor potential mucolipin 1) cause the lysosomal storage disorder, mucolipidosis type IV (MLIV). Here, we report that flies lacking the TRPML1 homolog displayed incomplete autophagy and reduced viability during the pupal period--a phase when animals rely on autophagy for nutrients. We show that TRPML was required for fusion of amphisomes with lysosomes, and its absence led to accumulation of vesicles of significantly larger volume and higher luminal Ca(2+). We also found that trpml(1) mutant cells showed decreased TORC1 (target of rapamycin complex 1) signaling and a concomitant upregulation of autophagy induction. Both of these defects in the mutants were reversed by genetically activating TORC1 or by feeding the larvae a high-protein diet. The high-protein diet also reduced the pupal lethality and the increased volume of acidic vesicles. Conversely, further inhibition of TORC1 activity by rapamycin exacerbated the mutant phenotypes. Finally, TORC1 exerted reciprocal control on TRPML function. A high-protein diet caused cortical localization of TRPML, and this effect was blocked by rapamycin. Our findings delineate the interrelationship between the TRPML and TORC1 pathways and raise the intriguing possibility that a high-protein diet might reduce the severity of MLIV.
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA.
authors.forename: Ching-On
authors.initials: CO
authors.lastname: Wong
authors.forename: Ruoxia
authors.initials: R
authors.lastname: Li
authors.forename: Craig
authors.initials: C
authors.lastname: Montell
authors.forename: Kartik
authors.initials: K
authors.lastname: Venkatachalam
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D008247:Lysosomes / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D008954:Models, Biological; D009154:Mutation; D014157:Transcription Factors / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051155:Wnt1 Protein / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; C570998:TORC1 protein complex, Drosophila; C578373:TRPML protein, Drosophila; D014157:Transcription Factors; D050051:Transient Receptor Potential Channels; D051155:Wnt1 Protein; C074622:wg protein, Drosophila; D002118:Calcium