TRPML1 links lysosomal calcium to autophagosome biogenesis through the activation of the CaMKKβ/VPS34 pathway

A. Scotto Rosato, S. Montefusco, C. Soldati, S. Di Paola, A. Capuozzo, J. Monfregola, E. Polishchuk, A. Amabile, C. Grimm, A. Lombardo, M. A. De Matteis, A. Ballabio and D. L. Medina ()
Additional contact information
A. Scotto Rosato: Telethon Institute of Genetics and Medicine (TIGEM)
S. Montefusco: Telethon Institute of Genetics and Medicine (TIGEM)
C. Soldati: Telethon Institute of Genetics and Medicine (TIGEM)
S. Di Paola: Telethon Institute of Genetics and Medicine (TIGEM)
A. Capuozzo: Telethon Institute of Genetics and Medicine (TIGEM)
J. Monfregola: Telethon Institute of Genetics and Medicine (TIGEM)
E. Polishchuk: Telethon Institute of Genetics and Medicine (TIGEM)
A. Amabile: Telethon Institute for Gene Therapy (SR-Tiget), Division of Regenerative Medicine, Stem Cells, and Gene Therapy, IRCCS San Raffaele Scientific Institute
C. Grimm: Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität
A. Lombardo: Telethon Institute for Gene Therapy (SR-Tiget), Division of Regenerative Medicine, Stem Cells, and Gene Therapy, IRCCS San Raffaele Scientific Institute
M. A. De Matteis: Telethon Institute of Genetics and Medicine (TIGEM)
A. Ballabio: Telethon Institute of Genetics and Medicine (TIGEM)
D. L. Medina: Telethon Institute of Genetics and Medicine (TIGEM)

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract The lysosomal calcium channel TRPML1, whose mutations cause the lysosomal storage disorder (LSD) mucolipidosis type IV (MLIV), contributes to upregulate autophagic genes by inducing the nuclear translocation of the transcription factor EB (TFEB). Here we show that TRPML1 activation also induces autophagic vesicle (AV) biogenesis through the generation of phosphatidylinositol 3-phosphate (PI3P) and the recruitment of essential PI3P-binding proteins to the nascent phagophore in a TFEB-independent manner. Thus, TRPML1 activation of phagophore formation requires the calcium-dependent kinase CaMKKβ and AMPK, which increase the activation of ULK1 and VPS34 autophagic protein complexes. Consistently, cells from MLIV patients show a reduced recruitment of PI3P-binding proteins to the phagophore during autophagy induction, suggesting that altered AV biogenesis is part of the pathological features of this disease. Together, we show that TRPML1 is a multistep regulator of autophagy that may be targeted for therapeutic purposes to treat LSDs and other autophagic disorders.

Date: 2019
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DOI: 10.1038/s41467-019-13572-w

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