Lysosomal retargeting of Myoferlin mitigates membrane stress to enable pancreatic cancer growth.

Animals Biomarkers, Tumor / genetics Calcium-Binding Proteins / genetics Cell Line, Tumor Cell Proliferation Gene Expression Regulation, Neoplastic Humans Intracellular Membranes / metabolism Lysosomes / genetics Membrane Proteins / genetics Mice, Inbred C57BL Mice, Transgenic Muscle Proteins / genetics Pancreatic Neoplasms / genetics Prognosis Signal Transduction Tumor Burden

Journal

Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575

Informations de publication

Date de publication:
03 2021
Historique:
received: 14 08 2020
accepted: 01 02 2021
pubmed: 10 3 2021
medline: 27 4 2021
entrez: 9 3 2021
Statut: ppublish

Résumé

Lysosomes must maintain the integrity of their limiting membrane to ensure efficient fusion with incoming organelles and degradation of substrates within their lumen. Pancreatic cancer cells upregulate lysosomal biogenesis to enhance nutrient recycling and stress resistance, but it is unknown whether dedicated programmes for maintaining the integrity of the lysosome membrane facilitate pancreatic cancer growth. Using proteomic-based organelle profiling, we identify the Ferlin family plasma membrane repair factor Myoferlin as selectively and highly enriched on the membrane of pancreatic cancer lysosomes. Mechanistically, lysosomal localization of Myoferlin is necessary and sufficient for the maintenance of lysosome health and provides an early acting protective system against membrane damage that is independent of the endosomal sorting complex required for transport (ESCRT)-mediated repair network. Myoferlin is upregulated in human pancreatic cancer, predicts poor survival and its ablation severely impairs lysosome function and tumour growth in vivo. Thus, retargeting of plasma membrane repair factors enhances the pro-oncogenic activities of the lysosome.

Identifiants

DOI: 10.1038/s41556-021-00644-7 PMID: 33686253 PMC: PMC9446896
pubmed: 33686253
doi: 10.1038/s41556-021-00644-7
pii: 10.1038/s41556-021-00644-7
pmc: PMC9446896
mid: NIHMS1828648
doi:

Substances chimiques

Biomarkers, Tumor 0
Calcium-Binding Proteins 0
MYOF protein, human 0
Membrane Proteins 0
Muscle Proteins 0
myoferlin protein, mouse 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

232-242

Subventions

Organisme : NCI NIH HHS
ID : DP2 CA216364
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA260249
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM127763
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM130995
Pays : United States

Références

Lawrence, R. E. & Zoncu, R. The lysosome as a cellular centre for signalling, metabolism and quality control. Nat. Cell Biol. 21, 133–142 (2019).
pubmed: 30602725 doi: 10.1038/s41556-018-0244-7
Perera, R. M. & Zoncu, R. The lysosome as a regulatory hub. Annu. Rev. Cell Dev. Biol. 32, 223–253 (2016).
pubmed: 27501449 doi: 10.1146/annurev-cellbio-111315-125125
Ballabio, A. & Bonifacino, J. S. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat. Rev. Mol. Cell Biol. 21, 101–118 (2020).
pubmed: 31768005 doi: 10.1038/s41580-019-0185-4
Commisso, C. et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637 (2013).
pubmed: 23665962 pmcid: 3810415 doi: 10.1038/nature12138
Kamphorst, J. J. et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75, 544–553 (2015).
pubmed: 25644265 pmcid: 4316379 doi: 10.1158/0008-5472.CAN-14-2211
Perera, R. M. et al. Transcriptional control of autophagy–lysosome function drives pancreatic cancer metabolism. Nature 524, 361–365 (2015).
pubmed: 26168401 pmcid: 5086585 doi: 10.1038/nature14587
Yang, A. et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 4, 905–913 (2014).
pubmed: 24875860 pmcid: 4125497 doi: 10.1158/2159-8290.CD-14-0362
Yang, S. et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 25, 717–729 (2011).
pubmed: 21406549 pmcid: 3070934 doi: 10.1101/gad.2016111
Yamamoto, K. et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature 581, 100–105 (2020).
pubmed: 32376951 pmcid: 7296553 doi: 10.1038/s41586-020-2229-5
Perera, R. M., Di Malta, C. & Ballabio, A. MiT/TFE family of transcription factors, lysosomes, and cancer. Annu Rev. Cancer Biol. 3, 203–222 (2019).
pubmed: 31650096 doi: 10.1146/annurev-cancerbio-030518-055835
Papadopoulos, C., Kravic, B. & Meyer, H. Repair or lysophagy: dealing with damaged Lysosomes. J. Mol. Biol. 432, 231–239 (2020).
pubmed: 31449799 doi: 10.1016/j.jmb.2019.08.010
Vietri, M., Radulovic, M. & Stenmark, H. The many functions of ESCRTs. Nat. Rev. Mol. Cell Biol. 21, 25–42 (2020).
pubmed: 31705132 doi: 10.1038/s41580-019-0177-4
Radulovic, M. et al. ESCRT-mediated lysosome repair precedes lysophagy and promotes cell survival. EMBO J. https://doi.org/10.15252/embj.201899753 (2018).
Skowyra, M. L., Schlesinger, P. H., Naismith, T. V. & Hanson, P. I. Triggered recruitment of ESCRT machinery promotes endolysosomal repair. Science https://doi.org/10.1126/science.aar5078 (2018).
Hung, Y. H., Chen, L. M., Yang, J. Y. & Yang, W. Y. Spatiotemporally controlled induction of autophagy-mediated lysosome turnover. Nat. Commun. 4, 2111 (2013).
pubmed: 23817530 doi: 10.1038/ncomms3111
Jia, J. et al. Galectins control mTOR in response to endomembrane damage. Mol. Cell 70, 120–135 (2018).
pubmed: 29625033 pmcid: 5911935 doi: 10.1016/j.molcel.2018.03.009
Maejima, I. et al. Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J. 32, 2336–2347 (2013).
pubmed: 23921551 pmcid: 3770333 doi: 10.1038/emboj.2013.171
Abu-Remaileh, M. et al. Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science 358, 807–813 (2017).
pubmed: 29074583 pmcid: 5704967 doi: 10.1126/science.aan6298
Zoncu, R. et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H
pubmed: 22053050 pmcid: 3211112 doi: 10.1126/science.1207056
Bansal, D. & Campbell, K. P. Dysferlin and the plasma membrane repair in muscular dystrophy. Trends Cell Biol. 14, 206–213 (2004).
pubmed: 15066638 doi: 10.1016/j.tcb.2004.03.001
Bansal, D. et al. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423, 168–172 (2003).
pubmed: 12736685 doi: 10.1038/nature01573
Davis, D. B., Delmonte, A. J., Ly, C. T. & McNally, E. M. Myoferlin, a candidate gene and potential modifier of muscular dystrophy. Hum. Mol. Genet. 9, 217–226 (2000).
pubmed: 10607832 doi: 10.1093/hmg/9.2.217
Doherty, K. R. et al. Normal myoblast fusion requires myoferlin. Development 132, 5565–5575 (2005).
pubmed: 16280346 doi: 10.1242/dev.02155
Lek, A., Evesson, F. J., Sutton, R. B., North, K. N. & Cooper, S. T. Ferlins: regulators of vesicle fusion for auditory neurotransmission, receptor trafficking and membrane repair. Traffic 13, 185–194 (2012).
pubmed: 21838746 doi: 10.1111/j.1600-0854.2011.01267.x
Bashir, R. et al. A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nat. Genet. 20, 37–42 (1998).
pubmed: 9731527 doi: 10.1038/1689
Liu, J. et al. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat. Genet. 20, 31–36 (1998).
pubmed: 9731526 doi: 10.1038/1682
Repnik, U. et al. L-leucyl-L-leucine methyl ester does not release cysteine cathepsins to the cytosol but inactivates them in transiently permeabilized lysosomes. J. Cell Sci. 130, 3124–3140 (2017).
pubmed: 28754686
Mercier, V. et al. Endosomal membrane tension regulates ESCRT-III-dependent intra-lumenal vesicle formation. Nat. Cell Biol. 22, 947–959 (2020).
pubmed: 32753669 pmcid: 7612185 doi: 10.1038/s41556-020-0546-4
Chauhan, S. et al. TRIMs and galectins globally cooperate and TRIM16 and Galectin-3 co-direct autophagy in endomembrane damage homeostasis. Dev. Cell 39, 13–27 (2016).
pubmed: 27693506 pmcid: 5104201 doi: 10.1016/j.devcel.2016.08.003
Thurston, T. L., Wandel, M. P., von Muhlinen, N., Foeglein, A. & Randow, F. Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482, 414–418 (2012).
pubmed: 22246324 pmcid: 3343631 doi: 10.1038/nature10744
Aits, S. et al. Sensitive detection of lysosomal membrane permeabilization by lysosomal galectin puncta assay. Autophagy 11, 1408–1424 (2015).
pubmed: 26114578 pmcid: 4590643 doi: 10.1080/15548627.2015.1063871
Kilpatrick, B. S., Eden, E. R., Hockey, L. N., Futter, C. E. & Patel, S. Methods for monitoring lysosomal morphology. Methods Cell. Biol. 126, 1–19 (2015).
pubmed: 25665438 doi: 10.1016/bs.mcb.2014.10.018
Platt, F. M., Boland, B. & van der Spoel, A. C. Lysosomal storage disorders: the cellular impact of lysosomal dysfunction. J. Cell Biol. 199, 723–734 (2012).
pubmed: 23185029 pmcid: 3514785 doi: 10.1083/jcb.201208152
Mauthe, M. et al. Chloroquine inhibits autophagic flux by decreasing autophagosome–lysosome fusion. Autophagy 14, 1435–1455 (2018).
pubmed: 29940786 pmcid: 6103682 doi: 10.1080/15548627.2018.1474314
Colom, A. et al. A fluorescent membrane tension probe. Nat. Chem. 10, 1118–1125 (2018).
pubmed: 30150727 pmcid: 6197433 doi: 10.1038/s41557-018-0127-3
Goujon, A. et al. Mechanosensitive fluorescent probes to image membrane tension in mitochondria, endoplasmic reticulum, and lysosomes. J. Am. Chem. Soc. 141, 3380–3384 (2019).
pubmed: 30744381 doi: 10.1021/jacs.8b13189
Lawrence, R. E. et al. A nutrient-induced affinity switch controls mTORC1 activation by its Rag GTPase–Ragulator lysosomal scaffold. Nat. Cell Biol. 20, 1052–1063 (2018).
pubmed: 30061680 pmcid: 6279252 doi: 10.1038/s41556-018-0148-6
Liberles, S. D., Diver, S. T., Austin, D. J. & Schreiber, S. L. Inducible gene expression and protein translocation using nontoxic ligands identified by a mammalian three-hybrid screen. Proc. Natl Acad. Sci. USA 94, 7825–7830 (1997).
pubmed: 9223271 pmcid: 21513 doi: 10.1073/pnas.94.15.7825
Davis, D. B., Doherty, K. R., Delmonte, A. J. & McNally, E. M. Calcium-sensitive phospholipid binding properties of normal and mutant ferlin C2 domains. J. Biol. Chem. 277, 22883–22888 (2002).
pubmed: 11959863 doi: 10.1074/jbc.M201858200
Marty, N. J., Holman, C. L., Abdullah, N. & Johnson, C. P. The C2 domains of otoferlin, dysferlin, and myoferlin alter the packing of lipid bilayers. Biochemistry 52, 5585–5592 (2013).
pubmed: 23859474 doi: 10.1021/bi400432f
Doherty, K. R. et al. The endocytic recycling protein EHD2 interacts with myoferlin to regulate myoblast fusion. J. Biol. Chem. 283, 20252–20260 (2008).
pubmed: 18502764 pmcid: 2459265 doi: 10.1074/jbc.M802306200
Lee, J. J. et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc. Natl Acad. Sci. USA 111, E3091–E3100 (2014).
pubmed: 25024225 pmcid: 4121834 doi: 10.1073/pnas.1411679111
Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).
pubmed: 14706336 doi: 10.1016/S1535-6108(03)00309-X
Weber, R. A. et al. Maintaining iron homeostasis is the key role of lysosomal acidity for cell proliferation. Mol. Cell 77, 645–655 e647 (2020).
pubmed: 31983508 pmcid: 7176020 doi: 10.1016/j.molcel.2020.01.003
Yambire, K. F. et al. Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo. eLife https://doi.org/10.7554/eLife.51031 (2019).
Xu, H. & Ren, D. Lysosomal physiology. Annu Rev. Physiol. 77, 57–80 (2015).
pubmed: 25668017 pmcid: 4524569 doi: 10.1146/annurev-physiol-021014-071649
Dong, R. et al. Endosome–ER contacts control actin nucleation and retromer function through VAP-dependent regulation of PI4P. Cell 166, 408–423 (2016).
pubmed: 27419871 pmcid: 4963242 doi: 10.1016/j.cell.2016.06.037
Lim, C. Y. et al. ER–lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann–Pick type C. Nat. Cell Biol. 21, 1206–1218 (2019).
pubmed: 31548609 pmcid: 6936960 doi: 10.1038/s41556-019-0391-5
Rademaker, G. et al. Myoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness. Oncogene 37, 4398–4412 (2018).
pubmed: 29720728 pmcid: 6085282 doi: 10.1038/s41388-018-0287-z
Rademaker, G. et al. Human colon cancer cells highly express myoferlin to maintain a fit mitochondrial network and escape p53-driven apoptosis. Oncogenesis 8, 21 (2019).
pubmed: 30850580 pmcid: 6408501 doi: 10.1038/s41389-019-0130-6
Petersen, N. H. et al. Transformation-associated changes in sphingolipid metabolism sensitize cells to lysosomal cell death induced by inhibitors of acid sphingomyelinase. Cancer Cell 24, 379–393 (2013).
pubmed: 24029234 doi: 10.1016/j.ccr.2013.08.003
Raudvere, U. et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists. Nucleic Acids Res. 47, W191–W198 (2019).
pubmed: 31066453 pmcid: 6602461 doi: 10.1093/nar/gkz369
Liang, X. et al. Rapid and highly efficient mammalian cell engineering via Cas9 protein transfection. J. Biotechnol. 208, 44–53 (2015).
pubmed: 26003884 doi: 10.1016/j.jbiotec.2015.04.024
Manuyakorn, A. et al. Cellular histone modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma: results from RTOG 9704. J. Clin. Oncol. 28, 1358–1365 (2010).
pubmed: 20142597 pmcid: 2834495 doi: 10.1200/JCO.2009.24.5639

Auteurs

Suprit Gupta (S)

Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
ORCID: 0000-0002-5861-9944

Julian Yano (J)

Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.

Vincent Mercier (V)

Department of Biochemistry, University of Geneva, Geneva, Switzerland.

Htet Htwe Htwe (HH)

Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.

Hijai R Shin (HR)

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
ORCID: 0000-0001-5642-4441

Gilles Rademaker (G)

Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.

Zeynep Cakir (Z)

Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.

Thomas Ituarte (T)

Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.

Kwun W Wen (KW)

Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.

Grace E Kim (GE)

Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.

Roberto Zoncu (R)

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
ORCID: 0000-0003-1611-1891

Aurélien Roux (A)

Department of Biochemistry, University of Geneva, Geneva, Switzerland.
ORCID: 0000-0002-6088-0711

David W Dawson (DW)

Department of Pathology and Laboratory Medicine and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA.

Rushika M Perera (RM)

Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA. rushika.perera@ucsf.edu.
Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. rushika.perera@ucsf.edu.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. rushika.perera@ucsf.edu.
ORCID: 0000-0003-2435-2273

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Marqueurs biologiques tumoraux › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de transport › Protéines de liaison au calcium › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Cellules › Structures cellulaires › Fractions subcellulaires › Membranes intracellulaires › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Vésicules cytoplasmiques › Lysosomes › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines contractiles › Protéines du muscle › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Diagnostic › Pronostic › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Lysosomal retargeting of Myoferlin mitigates...
questionsmedicales.fr › Techniques d'investigation › Charge tumorale › Lysosomal retargeting of Myoferlin mitigates...