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

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.

TRPML Cation Channels in Inflammation and Immunity

“…Both, enhanced lysosomal biogenesis and induction of autophagy promote the ability of cathepsin B deficient macrophages to get rid of ingested bacteria. TRPML3 has also been shown by several groups to be involved in autophagy (30)(31)(32)), suggesting that as described above for TRPML1 it may play similar roles in certain cell types. Evidence for an evolutionary conserved role of TRPMLs in bacterial clearance by macrophages comes from drosophila work.…”

Lysosomal Biology and Function: Modern View of Cellular Debris Bin

“…Retrograde mobilization of the lysosome is induced in a dynein-dynactin manner by TRPML1 and TMEM55B, which interact with C-Jun-amino-terminal kinase-interacting protein 4 (JIP4) ( Figure 6, step 4) [188]. A recent study demonstrated that TRPML1 activation induces biogenesis of autophagic vesicles by generating phosphatidylinositol 3-phosphate (PI3P) and recruiting PI3P-binding proteins to the nascent phagophore [189]. TRPML1 activity is also required for Ca 2+ -dependent centripetal transport of the lysosome towards the perinuclear region in HeLa cells and Cos1 cells, an effect independent of the Rab7-RIPL pathway [78].…”

Nanoparticle-Mediated Therapeutic Application for Modulation of Lysosomal Ion Channels and Functions

“…TRPML1 can regulate various cellular functions such as large particle phagocytosis through lysosomes [96], autophagosome biogenesis [161], elimination of bacterial pathogens through lysosome activation [162,163], bone remodeling in osteoclastogenesis [94], gastric acid secretion [93], and coronary arterial myocytes apoptosis [95]. In addition, the TRPML1 can reduce the enlargement of the lysosome by activating calmodulin [164].…”