Lysosomes are active sites to integrate cellular metabolism and signal transduction. A collection of proteins associated with the lysosome mediate these metabolic and signaling functions. Both lysosomal metabolism and lysosomal signaling have been linked to longevity regulation; however, how lysosomes adjust their protein composition to accommodate this regulation remains unclear. Using deep proteomic profiling, we systemically profiled lysosome-associated proteins linked with four different longevity mechanisms. We discovered the lysosomal recruitment of AMP-activated protein kinase and nucleoporin proteins and their requirements for longevity in response to increased lysosomal lipolysis. Through comparative proteomic analyses of lysosomes from different tissues and labeled with different markers, we further elucidated lysosomal heterogeneity across tissues as well as the increased enrichment of the Ragulator complex on Cystinosin-positive lysosomes. Together, this work uncovers lysosomal proteome heterogeneity across multiple scales and provides resources for understanding the contribution of lysosomal protein dynamics to signal transduction, organelle crosstalk, and organism longevity.

Department of Chemical Engineering and Genetics Stanford University Stanford United States

Department of Molecular and Cellular Biology Baylor College of Medicine Houston United States

Developmental Biology Graduate Program Baylor College of Medicine Houston United States

Huffington Center on Aging Baylor College of Medicine Houston United States

Institute for Chemistry Engineering and Medicine for Human Health Stanford University Stanford United States

Institute of Organic Chemistry and Biochemistry Prague Czech Republic

Janelia Research Campus Howard Hughes Medical Institute Ashburn United States

Molecular and Cellular Biology Graduate Program Baylor College of Medicine Houston United States

State Key Laboratory of Cellular Stress Biology School of Life Sciences Faculty of Medicine and Life Sciences Xiamen University Xiamen China

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doi: 10.1101/2022.10.16.512400 PubMed

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Abu-Remaileh M, Wyant GA, Kim C, Laqtom NN, Abbasi M, Chan SH, Freinkman E, Sabatini DM. Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science. 2017;358:807–813. doi: 10.1126/science.aan6298. PubMed DOI PMC

Andrzejewska Z, Nevo N, Thomas L, Chhuon C, Bailleux A, Chauvet V, Courtoy PJ, Chol M, Guerrera IC, Antignac C. Cystinosin is a component of the vacuolar H+-ATPase-ragulator-rag complex controlling mammalian target of rapamycin complex 1 signaling. Journal of the American Society of Nephrology. 2016;27:1678–1688. doi: 10.1681/ASN.2014090937. PubMed DOI PMC

Apfeld J, O’Connor G, McDonagh T, DiStefano PS, Curtis R. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes & Development. 2004;18:3004–3009. doi: 10.1101/gad.1255404. PubMed DOI PMC

Appelqvist H, Wäster P, Kågedal K, Öllinger K. The lysosome: from waste bag to potential therapeutic target. Journal of Molecular Cell Biology. 2013;5:214–226. doi: 10.1093/jmcb/mjt022. PubMed DOI

Ballabio A, Gieselmann V. Lysosomal disorders: from storage to cellular damage. Biochimica et Biophysica Acta. 2009;1793:684–696. doi: 10.1016/j.bbamcr.2008.12.001. PubMed DOI

Ballabio A, Bonifacino JS. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nature Reviews. Molecular Cell Biology. 2020;21:101–118. doi: 10.1038/s41580-019-0185-4. PubMed DOI

Berman JR, Kenyon C. Germ-cell loss extends C. elegans life span through regulation of DAF-16 by kri-1 and lipophilic-hormone signaling. Cell. 2006;124:1055–1068. doi: 10.1016/j.cell.2006.01.039. PubMed DOI

Braulke T, Bonifacino JS. Sorting of lysosomal proteins. Biochimica et Biophysica Acta. 2009;1793:605–614. doi: 10.1016/j.bbamcr.2008.10.016. PubMed DOI

Brown CA, Black SD. Membrane topology of mammalian cytochromes P-450 from liver endoplasmic reticulum. Determination by trypsinolysis of phenobarbital-treated microsomes. The Journal of Biological Chemistry. 1989;264:4442–4449. PubMed

Castellano BM, Thelen AM, Moldavski O, Feltes M, van der Welle REN, Mydock-McGrane L, Jiang X, van Eijkeren RJ, Davis OB, Louie SM, Perera RM, Covey DF, Nomura DK, Ory DS, Zoncu R. Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex. Science. 2017;355:1306–1311. doi: 10.1126/science.aag1417. PubMed DOI PMC

Crighton D, Wilkinson S, O’Prey J, Syed N, Smith P, Harrison PR, Gasco M, Garrone O, Crook T, Ryan KM. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell. 2006;126:121–134. doi: 10.1016/j.cell.2006.05.034. PubMed DOI

Cruciat CM, Ohkawara B, Acebron SP, Karaulanov E, Reinhard C, Ingelfinger D, Boutros M, Niehrs C. Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science. 2010;327:459–463. doi: 10.1126/science.1179802. PubMed DOI

Davidson SM, Vander Heiden MG. Critical functions of the lysosome in cancer biology. Annual Review of Pharmacology and Toxicology. 2017;57:481–507. doi: 10.1146/annurev-pharmtox-010715-103101. PubMed DOI

de Araujo MEG, Naschberger A, Fürnrohr BG, Stasyk T, Dunzendorfer-Matt T, Lechner S, Welti S, Kremser L, Shivalingaiah G, Offterdinger M, Lindner HH, Huber LA, Scheffzek K. Crystal structure of the human lysosomal mTORC1 scaffold complex and its impact on signaling. Science. 2017;358:377–381. doi: 10.1126/science.aao1583. PubMed DOI

De Franceschi N, Hamidi H, Alanko J, Sahgal P, Ivaska J. Integrin traffic - the update. Journal of Cell Science. 2015;128:839–852. doi: 10.1242/jcs.161653. PubMed DOI PMC

Deng DZQ, Verhage J, Neudorf C, Corbett-Detig R, Mekonen H, Castaldi PJ, Vollmers C. R2C2+UMI: Combining concatemeric consensus sequencing with unique molecular identifiers enables ultra-accurate sequencing of amplicons on oxford nanopore technologies sequencers. bioRxiv. 2023 doi: 10.1101/2023.08.19.553937. PubMed DOI PMC

Diao J, Liu R, Rong Y, Zhao M, Zhang J, Lai Y, Zhou Q, Wilz LM, Li J, Vivona S, Pfuetzner RA, Brunger AT, Zhong Q. ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature. 2015;520:563–566. doi: 10.1038/nature14147. PubMed DOI PMC

Eapen VV, Swarup S, Hoyer MJ, Paulo JA, Harper JW. Quantitative proteomics reveals the selectivity of ubiquitin-binding autophagy receptors in the turnover of damaged lysosomes by lysophagy. eLife. 2021;10:e72328. doi: 10.7554/eLife.72328. PubMed DOI PMC

Eskelinen EL. Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy. Molecular Aspects of Medicine. 2006;27:495–502. doi: 10.1016/j.mam.2006.08.005. PubMed DOI

Ewan LC, Jopling HM, Jia H, Mittar S, Bagherzadeh A, Howell GJ, Walker JH, Zachary IC, Ponnambalam S. Intrinsic tyrosine kinase activity is required for vascular endothelial growth factor receptor 2 ubiquitination, sorting and degradation in endothelial cells. Traffic. 2006;7:1270–1282. doi: 10.1111/j.1600-0854.2006.00462.x. PubMed DOI

Fehrenbacher N, Jäättelä M. Lysosomes as targets for cancer therapy. Cancer Research. 2005;65:2993–2995. doi: 10.1158/0008-5472.CAN-05-0476. PubMed DOI

Feng J, Bussière F, Hekimi S. Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans. Developmental Cell. 2001;1:633–644. doi: 10.1016/s1534-5807(01)00071-5. PubMed DOI

Folick A, Oakley HD, Yu Y, Armstrong EH, Kumari M, Sanor L, Moore DD, Ortlund EA, Zechner R, Wang MC. Aging lysosomal signaling molecules regulate longevity in Caenorhabditis elegans. Science. 2015;347:83–86. doi: 10.1126/science.1258857. PubMed DOI PMC

Forgac M. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nature Reviews. Molecular Cell Biology. 2007;8:917–929. doi: 10.1038/nrm2272. PubMed DOI

Gahl WA, Bashan N, Tietze F, Bernardini I, Schulman JD. Cystine transport is defective in isolated leukocyte lysosomes from patients with cystinosis. Science. 1982;217:1263–1265. doi: 10.1126/science.7112129. PubMed DOI

Gallet A, Therond PP. Temporal modulation of the Hedgehog morphogen gradient by a patched-dependent targeting to lysosomal compartment. Developmental Biology. 2005;277:51–62. doi: 10.1016/j.ydbio.2004.09.005. PubMed DOI

Gao Y, Chen Y, Zhan S, Zhang W, Xiong F, Ge W. Comprehensive proteome analysis of lysosomes reveals the diverse function of macrophages in immune responses. Oncotarget. 2017;8:7420–7440. doi: 10.18632/oncotarget.14558. PubMed DOI PMC

Grant B, Hirsh D. Receptor-mediated endocytosis in the Caenorhabditis elegans oocyte. Molecular Biology of the Cell. 1999;10:4311–4326. doi: 10.1091/mbc.10.12.4311. PubMed DOI PMC

Graves AR, Curran PK, Smith CL, Mindell JA. The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes. Nature. 2008;453:788–792. doi: 10.1038/nature06907. PubMed DOI

Hadwiger G, Dour S, Arur S, Fox P, Nonet ML. A monoclonal antibody toolkit for C. elegans. PLOS ONE. 2010;5:e10161. doi: 10.1371/journal.pone.0010161. PubMed DOI PMC

Hansen M, Rubinsztein DC, Walker DW. Autophagy as a promoter of longevity: insights from model organisms. Nature Reviews. Molecular Cell Biology. 2018;19:579–593. doi: 10.1038/s41580-018-0033-y. PubMed DOI PMC

Hartl FU, Martin J, Neupert W. Protein folding in the cell: the role of molecular chaperones Hsp70 and Hsp60. Annual Review of Biophysics and Biomolecular Structure. 1992;21:293–322. doi: 10.1146/annurev.bb.21.060192.001453. PubMed DOI

Itakura E, Kishi-Itakura C, Mizushima N. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell. 2012;151:1256–1269. doi: 10.1016/j.cell.2012.11.001. PubMed DOI

Ivanov A, Pawlikowski J, Manoharan I, van Tuyn J, Nelson DM, Rai TS, Shah PP, Hewitt G, Korolchuk VI, Passos JF, Wu H, Berger SL, Adams PD. Lysosome-mediated processing of chromatin in senescence. The Journal of Cell Biology. 2013;202:129–143. doi: 10.1083/jcb.201212110. PubMed DOI PMC

Johnson DE, Ostrowski P, Jaumouillé V, Grinstein S. The position of lysosomes within the cell determines their luminal pH. The Journal of Cell Biology. 2016;212:677–692. doi: 10.1083/jcb.201507112. PubMed DOI PMC

Jonas AJ, Greene AA, Smith ML, Schneider JA. Cystine accumulation and loss in normal, heterozygous, and cystinotic fibroblasts. PNAS. 1982;79:4442–4445. doi: 10.1073/pnas.79.14.4442. PubMed DOI PMC

Jouandin P, Marelja Z, Shih YH, Parkhitko AA, Dambowsky M, Asara JM, Nemazanyy I, Dibble CC, Simons M, Perrimon N. Lysosomal cystine mobilization shapes the response of TORC1 and tissue growth to fasting. Science. 2022;375:eabc4203. doi: 10.1126/science.abc4203. PubMed DOI PMC

Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K, Bates R, Žídek A, Potapenko A, Bridgland A, Meyer C, Kohl SAA, Ballard AJ, Cowie A, Romera-Paredes B, Nikolov S, Jain R, Adler J, Back T, Petersen S, Reiman D, Clancy E, Zielinski M, Steinegger M, Pacholska M, Berghammer T, Bodenstein S, Silver D, Vinyals O, Senior AW, Kavukcuoglu K, Kohli P, Hassabis D. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596:583–589. doi: 10.1038/s41586-021-03819-2. PubMed DOI PMC

Kalatzis V, Cherqui S, Antignac C, Gasnier B. Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter. The EMBO Journal. 2001;20:5940–5949. doi: 10.1093/emboj/20.21.5940. PubMed DOI PMC

Kane PM. Disassembly and reassembly of the yeast vacuolar H(+)-ATPase in vivo. The Journal of Biological Chemistry. 1995;270:17025–17032. PubMed

Kang DS, Tian X, Benovic JL. Role of β-arrestins and arrestin domain-containing proteins in G protein-coupled receptor trafficking. Current Opinion in Cell Biology. 2014;27:63–71. doi: 10.1016/j.ceb.2013.11.005. PubMed DOI PMC

Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature. 1993;366:461–464. doi: 10.1038/366461a0. PubMed DOI

Khan AS, Frigo DE. A spatiotemporal hypothesis for the regulation, role, and targeting of AMPK in prostate cancer. Nature Reviews Urology. 2017;14:164–180. doi: 10.1038/nrurol.2016.272. PubMed DOI PMC

Lapierre LR, Gelino S, Meléndez A, Hansen M. Autophagy and lipid metabolism coordinately modulate life span in germline-less C. elegans. Current Biology. 2011;21:1507–1514. doi: 10.1016/j.cub.2011.07.042. PubMed DOI PMC

Laqtom NN, Dong W, Medoh UN, Cangelosi AL, Dharamdasani V, Chan SH, Kunchok T, Lewis CA, Heinze I, Tang R, Grimm C, Dang Do AN, Porter FD, Ori A, Sabatini DM, Abu-Remaileh M. CLN3 is required for the clearance of glycerophosphodiesters from lysosomes. Nature. 2022;609:1005–1011. doi: 10.1038/s41586-022-05221-y. PubMed DOI PMC

Lawrence RE, Zoncu R. The lysosome as a cellular centre for signalling, metabolism and quality control. Nature Cell Biology. 2019;21:133–142. doi: 10.1038/s41556-018-0244-7. PubMed DOI

Le S, Josse J, Husson F. FactoMineR: An R package for multivariate analysis. Journal of Statistical Software. 2008;25:1–18. doi: 10.18637/jss.v025.i01. DOI

Léger-Silvestre I, Caffrey JM, Dawaliby R, Alvarez-Arias DA, Gas N, Bertolone SJ, Gleizes PE, Ellis SR. Specific role for yeast homologs of the diamond blackfan anemia-associated Rps19 protein in ribosome synthesis. The Journal of Biological Chemistry. 2005;280:38177–38185. doi: 10.1074/jbc.M506916200. PubMed DOI

Li RJ, Xu J, Fu C, Zhang J, Zheng YG, Jia H, Liu JO. Regulation of mTORC1 by lysosomal calcium and calmodulin. eLife. 2016;5:e19360. doi: 10.7554/eLife.19360. PubMed DOI PMC

Lin HJ, Herman P, Kang JS, Lakowicz JR. Fluorescence lifetime characterization of novel low-pH probes. Analytical Biochemistry. 2001;294:118–125. doi: 10.1006/abio.2001.5155. PubMed DOI PMC

Linkert M, Rueden CT, Allan C, Burel JM, Moore W, Patterson A, Loranger B, Moore J, Neves C, Macdonald D, Tarkowska A, Sticco C, Hill E, Rossner M, Eliceiri KW, Swedlow JR. Metadata matters: access to image data in the real world. The Journal of Cell Biology. 2010;189:777–782. doi: 10.1083/jcb.201004104. PubMed DOI PMC

Lübke T, Lobel P, Sleat DE. Proteomics of the lysosome. Biochimica et Biophysica Acta. 2009;1793:625–635. doi: 10.1016/j.bbamcr.2008.09.018. PubMed DOI PMC

Ma Z, Thomas KS, Webb DJ, Moravec R, Salicioni AM, Mars WM, Gonias SL. Regulation of Rac1 activation by the low density lipoprotein receptor-related protein. The Journal of Cell Biology. 2002;159:1061–1070. doi: 10.1083/jcb.200207070. PubMed DOI PMC

Markmann S, Krambeck S, Hughes CJ, Mirzaian M, Aerts J, Saftig P, Schweizer M, Vissers JPC, Braulke T, Damme M. Quantitative proteome analysis of mouse liver lysosomes provides evidence for mannose 6-phosphate-independent targeting mechanisms of acid hydrolases in mucolipidosis II. Molecular & Cellular Proteomics. 2017;16:438–450. doi: 10.1074/mcp.M116.063636. PubMed DOI PMC

Martins R, Lithgow GJ, Link W. Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell. 2016;15:196–207. doi: 10.1111/acel.12427. PubMed DOI PMC

Mayer MP. Gymnastics of molecular chaperones. Molecular Cell. 2010;39:321–331. doi: 10.1016/j.molcel.2010.07.012. PubMed DOI

McGuire CM, Forgac M. Glucose starvation increases V-ATPase assembly and activity in mammalian cells through AMP kinase and phosphatidylinositide 3-kinase/Akt signaling. The Journal of Biological Chemistry. 2018;293:9113–9123. doi: 10.1074/jbc.RA117.001327. PubMed DOI PMC

Mijaljica D, Devenish RJ. Nucleophagy at a glance. Journal of Cell Science. 2013;126:4325–4330. doi: 10.1242/jcs.133090. PubMed DOI

Mutlu AS, Gao SM, Zhang H, Wang MC. Olfactory specificity regulates lipid metabolism through neuroendocrine signaling in Caenorhabditis elegans. Nature Communications. 2020;11:1450. doi: 10.1038/s41467-020-15296-8. PubMed DOI PMC

Nakae I, Fujino T, Kobayashi T, Sasaki A, Kikko Y, Fukuyama M, Gengyo-Ando K, Mitani S, Kontani K, Katada T. The arf-like GTPase Arl8 mediates delivery of endocytosed macromolecules to lysosomes in Caenorhabditis elegans. Molecular Biology of the Cell. 2010;21:2434–2442. doi: 10.1091/mbc.e09-12-1010. PubMed DOI PMC

Nakamura S, Yoshimori T. Autophagy and Longevity. Molecules and Cells. 2018;41:65–72. doi: 10.14348/molcells.2018.2333. PubMed DOI PMC

Navarro-Romero A, Montpeyó M, Martinez-Vicente M. The emerging role of the lysosome in parkinson’s disease. Cells. 2020;9:2399. doi: 10.3390/cells9112399. PubMed DOI PMC

Nicoli E-R, Weston MR, Hackbarth M, Becerril A, Larson A, Zein WM, Baker PR, Burke JD, Dorward H, Davids M, Huang Y, Adams DR, Zerfas PM, Chen D, Markello TC, Toro C, Wood T, Elliott G, Vu M, Zheng W, Garrett LJ, Tifft CJ, Gahl WA, Day-Salvatore DL, Mindell JA, Malicdan MCV, Undiagnosed Diseases Network Lysosomal storage and albinism due to effects of a de novo CLCN7 variant on lysosomal acidification. American Journal of Human Genetics. 2019;104:1127–1138. doi: 10.1016/j.ajhg.2019.04.008. PubMed DOI PMC

Nishimura T, Kaizuka T, Cadwell K, Sahani MH, Saitoh T, Akira S, Virgin HW, Mizushima N. FIP200 regulates targeting of Atg16L1 to the isolation membrane. EMBO Reports. 2013;14:284–291. doi: 10.1038/embor.2013.6. PubMed DOI PMC

Nixon RA, Cataldo AM. Lysosomal system pathways: genes to neurodegeneration in Alzheimer’s disease. Journal of Alzheimer’s Disease. 2006;9:277–289. doi: 10.3233/jad-2006-9s331. PubMed DOI

O’Rourke EJ, Kuballa P, Xavier R, Ruvkun G. ω-6 Polyunsaturated fatty acids extend life span through the activation of autophagy. Genes & Development. 2013;27:429–440. doi: 10.1101/gad.205294.112. PubMed DOI PMC

Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. UCSF Chimera--a visualization system for exploratory research and analysis. Journal of Computational Chemistry. 2004;25:1605–1612. doi: 10.1002/jcc.20084. PubMed DOI

Platt FM, Boland B, van der Spoel AC. The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction. The Journal of Cell Biology. 2012;199:723–734. doi: 10.1083/jcb.201208152. PubMed DOI PMC

Popovic D, Dikic I. TBC1D5 and the AP2 complex regulate ATG9 trafficking and initiation of autophagy. EMBO Reports. 2014;15:392–401. doi: 10.1002/embr.201337995. PubMed DOI PMC

Pu J, Guardia CM, Keren-Kaplan T, Bonifacino JS. Mechanisms and functions of lysosome positioning. Journal of Cell Science. 2016;129:4329–4339. doi: 10.1242/jcs.196287. PubMed DOI PMC

Ramachandran PV, Savini M, Folick AK, Hu K, Masand R, Graham BH, Wang MC. Lysosomal signaling promotes longevity by adjusting mitochondrial activity. Developmental Cell. 2019;48:685–696. doi: 10.1016/j.devcel.2018.12.022. PubMed DOI PMC

Ratto E, Chowdhury SR, Siefert NS, Schneider M, Wittmann M, Helm D, Palm W. Direct control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly. Nature Communications. 2022;13:4848. doi: 10.1038/s41467-022-32515-6. PubMed DOI PMC

Rebsamen M, Pochini L, Stasyk T, de Araújo MEG, Galluccio M, Kandasamy RK, Snijder B, Fauster A, Rudashevskaya EL, Bruckner M, Scorzoni S, Filipek PA, Huber KVM, Bigenzahn JW, Heinz LX, Kraft C, Bennett KL, Indiveri C, Huber LA, Superti-Furga G. SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature. 2015;519:477–481. doi: 10.1038/nature14107. PubMed DOI PMC

Saltzman AB, Leng M, Bhatt B, Singh P, Chan DW, Dobrolecki L, Chandrasekaran H, Choi JM, Jain A, Jung SY, Lewis MT, Ellis MJ, Malovannaya A. gpGrouper: A peptide grouping algorithm for gene-centric inference and quantitation of bottom-up proteomics data. Molecular & Cellular Proteomics. 2018;17:2270–2283. doi: 10.1074/mcp.TIR118.000850. PubMed DOI PMC

Savini M, Zhao Q, Wang MC. Lysosomes: Signaling hubs for metabolic sensing and longevity. Trends in Cell Biology. 2019;29:876–887. doi: 10.1016/j.tcb.2019.08.008. PubMed DOI PMC

Savini M, Folick A, Lee YT, Jin F, Cuevas A, Tillman MC, Duffy JD, Zhao Q, Neve IA, Hu PW, Yu Y, Zhang Q, Ye Y, Mair WB, Wang J, Han L, Ortlund EA, Wang MC. Lysosome lipid signalling from the periphery to neurons regulates longevity. Nature Cell Biology. 2022;24:906–916. doi: 10.1038/s41556-022-00926-8. PubMed DOI PMC

Schröder BA, Wrocklage C, Hasilik A, Saftig P. The proteome of lysosomes. Proteomics. 2010;10:4053–4076. doi: 10.1002/pmic.201000196. PubMed DOI

Snyder JC, Rochelle LK, Lyerly HK, Caron MG, Barak LS. Constitutive internalization of the leucine-rich G protein-coupled receptor-5 (LGR5) to the trans-Golgi network. The Journal of Biological Chemistry. 2013;288:10286–10297. doi: 10.1074/jbc.M112.447540. PubMed DOI PMC

Stiernagle T. Maintenance of C. elegans. WormBook. 2006;11:1–11. doi: 10.1895/wormbook.1.101.1. PubMed DOI PMC

Stransky LA, Forgac M. Amino acid availability modulates vacuolar H+-ATPase assembly. The Journal of Biological Chemistry. 2015;290:27360–27369. doi: 10.1074/jbc.M115.659128. PubMed DOI PMC

Sun Y, Li M, Zhao D, Li X, Yang C, Wang X. Lysosome activity is modulated by multiple longevity pathways and is important for lifespan extension in C. elegans. eLife. 2020;9:e55745. doi: 10.7554/eLife.55745. PubMed DOI PMC

Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, Turk B, Turk D. Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochimica et Biophysica Acta. 2012;1824:68–88. doi: 10.1016/j.bbapap.2011.10.002. PubMed DOI PMC

Varadi M, Anyango S, Deshpande M, Nair S, Natassia C, Yordanova G, Yuan D, Stroe O, Wood G, Laydon A, Žídek A, Green T, Tunyasuvunakool K, Petersen S, Jumper J, Clancy E, Green R, Vora A, Lutfi M, Figurnov M, Cowie A, Hobbs N, Kohli P, Kleywegt G, Birney E, Hassabis D, Velankar S. AlphaFold protein structure database: Massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Research. 2022;50:D439–D444. doi: 10.1093/nar/gkab1061. PubMed DOI PMC

Vasu S, Shah S, Orjalo A, Park M, Fischer WH, Forbes DJ. Novel vertebrate nucleoporins Nup133 and Nup160 play a role in mRNA export. The Journal of Cell Biology. 2001;155:339–354. doi: 10.1083/jcb.200108007. PubMed DOI PMC

Wang MC, O’Rourke EJ, Ruvkun G. Fat metabolism links germline stem cells and longevity in C. elegans. Science. 2008;322:957–960. doi: 10.1126/science.1162011. PubMed DOI PMC

Wang S, Tsun ZY, Wolfson RL, Shen K, Wyant GA, Plovanich ME, Yuan ED, Jones TD, Chantranupong L, Comb W, Wang T, Bar-Peled L, Zoncu R, Straub C, Kim C, Park J, Sabatini BL, Sabatini DM. Metabolism lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science. 2015;347:188–194. doi: 10.1126/science.1257132. PubMed DOI PMC

Webb BA, Aloisio FM, Charafeddine RA, Cook J, Wittmann T, Barber DL, Jäättelä M. pHLARE: a new biosensor reveals decreased lysosome pH in cancer cells. Molecular Biology of the Cell. 2021;32:131–142. doi: 10.1091/mbc.E20-06-0383. PubMed DOI PMC

Willett R, Martina JA, Zewe JP, Wills R, Hammond GRV, Puertollano R. TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes. Nature Communications. 2017;8:1580. doi: 10.1038/s41467-017-01871-z. PubMed DOI PMC

Wyant GA, Abu-Remaileh M, Wolfson RL, Chen WW, Freinkman E, Danai LV, Vander Heiden MG, Sabatini DM. mTORC1 activator SLC38A9 is required to efflux essential amino acids from lysosomes and use protein as a nutrient. Cell. 2017;171:642–654. doi: 10.1016/j.cell.2017.09.046. PubMed DOI PMC

Zhang CS, Jiang B, Li M, Zhu M, Peng Y, Zhang YL, Wu YQ, Li TY, Liang Y, Lu Z, Lian G, Liu Q, Guo H, Yin Z, Ye Z, Han J, Wu JW, Yin H, Lin SY, Lin SC. The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metabolism. 2014;20:526–540. doi: 10.1016/j.cmet.2014.06.014. PubMed DOI