How NPC1 Loss Twists the TORCque of Lysosomes

Niemann-Pick type C is a neurological disorder caused by mutations in the lysosome cholesterol exporter NPC1. In this issue of Developmental Cell, Davis et al. dissect how NPC1 loss elevates mTORC1 signaling, and demonstrate that suppression signaling can rescue disease pathology NPC1-deficient cell models. Lysosomes are key degradation organelles. As centers catabolic metabolism, they receive regular deliveries proteins lipids via autophagy endomembrane trafficking. Once internalized into lysosome, these biomaterials digested more basic metabolites fuel anabolic thus driving metabolic recycling central to cellular growth homeostasis (Lawrence Zoncu, 2019Lawrence R.E. Zoncu R. The as centre for signalling, metabolism quality control.Nat. Cell Biol. 2019; 21: 133-142Crossref PubMed Scopus (273) Google Scholar). Perhaps due intricate balance between genetic defects function cause myriad so-called lysosomal storage disorders (LSDs) impact various tissues body. One most studied LSDs (NPC), loss-of-function within gene encoding transporter facilitates export from interior cytoplasm, where it eventually transported other organelles serve diverse roles (Davies al., 2000Davies J.P. Chen F.W. Ioannou Y.A. Transmembrane molecular pump activity C1 protein.Science. 2000; 290: 2295-2298Crossref (250) Scholar; Das 2014Das A. Brown M.S. Anderson D.D. Goldstein J.L. Radhakrishnan Three pools plasma membrane their relation homeostasis.eLife. 2014; 3: e02882Crossref (170) many cells bulk endocytic uptake low-density lipoprotein (Brown Goldstein, 1986Brown A receptor-mediated pathway homeostasis.Science. 1986; 232: 34-47Crossref (4217) Scholar), plays critical role retrieval homeostasis. Consequently, has been long known deficiency results aberrant morphology an accumulation lysosomes. How ultimately contributes NPC disease, however, less clear. insight mystery came work indicating be sensed at lysosomes drive (Castellano 2017Castellano B.M. Thelen A.M. Moldavski O. Feltes M. van der Welle Mydock-McGrane L. Jiang X. Eijkeren R.J. O.B. Louie S.M. al.Lysosomal activates SLC38A9-Niemann-Pick complex.Science. 2017; 355: 1306-1311Crossref (202) major regulators knowledge sense not only amino acids but also cholesterol, fine-tune activity, expanded our understanding multi-pronged surveyors metabolites. To mechanistically probe cholesterol-NPC1-mTORC1 axis relates 2020Davis Shin H.R. Lim C. Wu E.Y. Kukurugya Maher C.F. Perera R.M. Ordonez M.P. NPC1-mTORC1 Signaling Couples Cholesterol Sensing Organelle Homeostasis Is Targetable Pathway Type C.Dev. Cell. 2020; 56 (this issue): 260-276Google Scholar took biochemical approach conducted label-free proteomics on isolated control knockout (Davis Surprisingly, null accumulated proteins. This required functional autophagy, suggesting were aberrantly accumulating substrates autophagic turnover. These contained fewer hydrolases, hinting undigested biomaterials. What would effect such substrate lysosomes? consequence could formation “microtears” membrane, which have proposed dysfunction (Jia 2020Jia J. Claude-Taupin Gu Y. Choi S.W. Peters Bissa B. Mudd M.H. Allers Pallikkuth S. Lidke K.A. al.Galectin-3 Coordinates Cellular System Lysosomal Repair Removal.Dev. 52: 69-87.e8Abstract Full Text PDF (57) investigate whether similar microtears occurring model, monitored components ESCRT-III complex. unique protein complex localizes compartments, its spiral-like structure, thought “zipper up” gaps (Skowyra 2018Skowyra M.L. Schlesinger P.H. Naismith T.V. Hanson P.I. Triggered recruitment ESCRT machinery promotes endolysosomal repair.Science. 2018; 360: eaar5078Crossref (128) Remarkably, elevated immunoblotting, visualized following brief treatment with membrane-disrupting chemical LLMOe. Importantly, effects re-expressing wild-type mutants lacking transport function. collectively suggested NPC1’s was necessary So, accumulation, perturbed integrity. question remains: do pathologies contribute state? this, authors focused observation: signaling. Hypothesizing hyper-active may culprit tested reintroduction wild or suppress Indeed, transport-competent restore normal supporting notion hyperactive They then asked if suppressing pathology. First, examined levels sphingolipids Torin1-treated cells, potent inhibitor. Interestingly, inhibition did alter lysosomes, dysregulation occurred downstream accumulation. Strikingly indicated Torin1 addition knockdown component Lamtor5. line rescued damage. Thus, emerging model perturbations flux simply byproduct per se. Using induced pluripotent stem differentiated neurons, showed similarly neuron-like Could there processes altered hyperactivation? mitochondrial biogenesis, turnover mitophagy underlie numerous diseases. affected ability maintain manifested delivering mitochondria exhibited fragmentation. supports perturbs integrity well mitophagy, promoting (Figure 1). Collectively, study dissects hyperactivity shown causative Furthermore, indicates events disease-related Still, questions remain. precisely what about pathogenic cells. drives translation. buildup cannot efficiently clear? Alternatively, mTORC1-driven remodeling, starve specific metabolites, defective unable supply? any case, provides further evidence delicate coordinated It establishes potentially novel therapeutic target treating disease. declare no competing interests. CDavis al.Developmental CellDecember 11, 2020In BriefNiemann-Pick devastating neurodegenerative Through organelle proteomics, identify degradative structural Aberrant restores Full-Text