Lysosomal Retargeting of Myoferlin Mitigates Membrane Stress to Enable Pancreatic Cancer Growth

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2021 Mar 9

PMID 33686253

Citations 27

Authors

Suprit Gupta

Julian Yano

Vincent Mercier

Htet Htwe Htwe

Hijai R Shin

Gilles Rademaker

Zeynep Cakir

Thomas Ituarte

Kwun W Wen

Grace E Kim

Roberto Zoncu

Aurelien Roux

David W Dawson

Rushika M Perera

Affiliations

Soon will be listed here.

Abstract

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.

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References

Lawrence R, Zoncu R . The lysosome as a cellular centre for signalling, metabolism and quality control. Nat Cell Biol. 2019; 21(2):133-142. DOI: 10.1038/s41556-018-0244-7. View

Perera R, Zoncu R . The Lysosome as a Regulatory Hub. Annu Rev Cell Dev Biol. 2016; 32:223-253. PMC: 9345128. DOI: 10.1146/annurev-cellbio-111315-125125. View

Ballabio A, Bonifacino J . Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol Cell Biol. 2019; 21(2):101-118. DOI: 10.1038/s41580-019-0185-4. View

Commisso C, Davidson S, Soydaner-Azeloglu R, Parker S, Kamphorst J, Hackett S . Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature. 2013; 497(7451):633-7. PMC: 3810415. DOI: 10.1038/nature12138. View

Kamphorst J, Nofal M, Commisso C, Hackett S, Lu W, Grabocka E . Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 2015; 75(3):544-53. PMC: 4316379. DOI: 10.1158/0008-5472.CAN-14-2211. View

Perera R, Stoykova S, Nicolay B, Ross K, Fitamant J, Boukhali M . Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature. 2015; 524(7565):361-5. PMC: 5086585. DOI: 10.1038/nature14587. View

Yang A, Rajeshkumar N, Wang X, Yabuuchi S, Alexander B, Chu G . Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 2014; 4(8):905-13. PMC: 4125497. DOI: 10.1158/2159-8290.CD-14-0362. View

Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H . Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011; 25(7):717-29. PMC: 3070934. DOI: 10.1101/gad.2016111. View

Yamamoto K, Venida A, Yano J, Biancur D, Kakiuchi M, Gupta S . Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature. 2020; 581(7806):100-105. PMC: 7296553. DOI: 10.1038/s41586-020-2229-5. View

10.

Perera R, Di Malta C, Ballabio A . MiT/TFE Family of Transcription Factors, Lysosomes, and Cancer. Annu Rev Cancer Biol. 2019; 3:203-222. PMC: 6812561. DOI: 10.1146/annurev-cancerbio-030518-055835. View

11.

Papadopoulos C, Kravic B, Meyer H . Repair or Lysophagy: Dealing with Damaged Lysosomes. J Mol Biol. 2019; 432(1):231-239. DOI: 10.1016/j.jmb.2019.08.010. View

12.

Vietri M, Radulovic M, Stenmark H . The many functions of ESCRTs. Nat Rev Mol Cell Biol. 2019; 21(1):25-42. DOI: 10.1038/s41580-019-0177-4. View

13.

Hung Y, Chen L, Yang J, Yang W . Spatiotemporally controlled induction of autophagy-mediated lysosome turnover. Nat Commun. 2013; 4:2111. DOI: 10.1038/ncomms3111. View

14.

Jia J, Abudu Y, Claude-Taupin A, Gu Y, Kumar S, Choi S . Galectins Control mTOR in Response to Endomembrane Damage. Mol Cell. 2018; 70(1):120-135.e8. PMC: 5911935. DOI: 10.1016/j.molcel.2018.03.009. View

15.

Maejima I, Takahashi A, Omori H, Kimura T, Takabatake Y, Saitoh T . Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J. 2013; 32(17):2336-47. PMC: 3770333. DOI: 10.1038/emboj.2013.171. View

16.

Abu-Remaileh M, Wyant G, Kim C, Laqtom N, Abbasi M, Chan S . Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science. 2017; 358(6364):807-813. PMC: 5704967. DOI: 10.1126/science.aan6298. View

17.

Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini D . mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science. 2011; 334(6056):678-83. PMC: 3211112. DOI: 10.1126/science.1207056. View

18.

Bansal D, Campbell K . Dysferlin and the plasma membrane repair in muscular dystrophy. Trends Cell Biol. 2004; 14(4):206-13. DOI: 10.1016/j.tcb.2004.03.001. View

19.

Bansal D, Miyake K, Vogel S, Groh S, Chen C, Williamson R . Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature. 2003; 423(6936):168-72. DOI: 10.1038/nature01573. View

20.

Davis D, Delmonte A, Ly C, MCNALLY E . Myoferlin, a candidate gene and potential modifier of muscular dystrophy. Hum Mol Genet. 1999; 9(2):217-26. DOI: 10.1093/hmg/9.2.217. View