Follicular lymphoma-associated mutations in the V-ATPase chaperone VMA21 activate autophagy creating a targetable dependency

References

• Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood. 2006 Jan 1;107(1):265–276.
   PubMed Web of Science ®Google Scholar
• Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the national lymphocare study. J Clin Oncol. 2015 Aug 10;33(23):2516–2522.
   PubMed Web of Science ®Google Scholar
• Kridel R, Sehn LH, Gascoyne RD, et al. Pathogenesis of follicular lymphoma. J Clin Invest. 2012 Oct 1;122(10):3424–3431.
   PubMed Web of Science ®Google Scholar
• Kahl BS, Yang DT. Follicular lymphoma: evolving therapeutic strategies. Blood. 2016 Apr 28;127(17):2055–2063.
   PubMed Web of Science ®Google Scholar
• Kuppers R, Stevenson FK. Critical influences on the pathogenesis of follicular lymphoma. Blood. 2018 May 24;131(21):2297–2306.
   PubMed Web of Science ®Google Scholar
• Okosun J, Wolfson RL, Wang J, et al. Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma. Nat Genet. 2016 Feb;48(2):183–188.
   PubMed Web of Science ®Google Scholar
• Ying ZX, Jin M, Peterson LF, et al. Recurrent Mutations in the MTOR Regulator RRAGC in follicular lymphoma. Clin Cancer Res. 2016 Nov 1;22(21):5383–5393.
   PubMed Web of Science ®Google Scholar
• Oricchio E, Katanayeva N, Donaldson MC, et al. Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma. Sci Transl Med. 2017;Jun 28;9(396): eaak9969.
   PubMed Web of Science ®Google Scholar
• Bar-Peled L, Schweitzer LD, Zoncu R, et al. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell. 2012 Sep 14;150(6):1196–1208.
   PubMed Web of Science ®Google Scholar
• Sabatini DM. Twenty-five years of mTOR: uncovering the link from nutrients to growth. Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):11818–11825.
   PubMed Web of Science ®Google Scholar
• Kim E, Goraksha-Hicks P, Li L, et al. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol. 2008 Aug;10(8):935–945.
   PubMed Web of Science ®Google Scholar
• Sancak Y, Peterson TR, Shaul YD, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. 2008 Jun 13;320(5882):1496–1501.
   PubMed Web of Science ®Google Scholar
• Wang S, Tsun ZY, Wolfson RL, et al. Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science. 2015 Jan 9;347(6218):188–194.
   PubMed Web of Science ®Google Scholar
• Rebsamen M, Pochini L, Stasyk T, et al. SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature. 2015 Mar 26;519(7544):477–481.
   PubMed Web of Science ®Google Scholar
• Jung J, Genau HM, Behrends C, et al. Amino acid-dependent mTORC1 regulation by the lysosomal membrane protein SLC38A9. Mol Cell Biol. 2015 Jul;35(14):2479–2494.
   PubMed Web of Science ®Google Scholar
• Zoncu R, Bar-Peled L, Efeyan A, et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science. 2011 Nov 4;334(6056):678–683.
   PubMed Web of Science ®Google Scholar
• Green MR, Kihira S, Liu CL, et al. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proc Natl Acad Sci U S A. 2015 Mar 10;112(10):E1116–25.
   PubMed Web of Science ®Google Scholar
• Wang F, Gatica D, Ying ZX, et al. Follicular lymphoma-associated mutations in vacuolar ATPase ATP6V1B2 activate autophagic flux and mTOR. J Clin Invest. 2019 Mar 4;129(4):1626–1640.
   PubMed Web of Science ®Google Scholar
• Cotter K, Stransky L, McGuire C, et al. Recent Insights into the Structure, Regulation, and Function of the V-ATPases. Trends Biochem Sci. 2015 Oct;40(10):611–622.
   PubMed Web of Science ®Google Scholar
• Wang R, Long T, Hassan A, et al. Cryo-EM structures of intact V-ATPase from bovine brain. Nat Commun. 2020 Aug 6;11(1):3921.
   PubMed Web of Science ®Google Scholar
• Abbas YM, Wu D, Bueler SA, et al. Structure of V-ATPase from the mammalian brain. Science. 2020 Mar 13;367(6483):1240–1246.
   PubMed Web of Science ®Google Scholar
• Ballabio A, Bonifacino JS. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol Cell Biol. 2020 Feb;21(2):101–118.
   PubMed Web of Science ®Google Scholar
• Malkus P, Graham LA, Stevens TH, et al. Role of Vma21p in assembly and transport of the yeast vacuolar ATPase. Mol Biol Cell. 2004 Nov;15(11):5075–5091.
   PubMed Web of Science ®Google Scholar
• Ryan M, Graham LA, Stevens TH, et al. Voa1p functions in V-ATPase assembly in the yeast endoplasmic reticulum. Mol Biol Cell. 2008 Dec;19(12):5131–5142.
   PubMed Web of Science ®Google Scholar
• Guida MC, Hermle T, Graham LA, et al. ATP6AP2 functions as a V-ATPase assembly factor in the endoplasmic reticulum. Mol Biol Cell. 2018 Sep 1;29(18):2156–2164.
   PubMed Web of Science ®Google Scholar
• Wang L, Wu D, Robinson CV, et al. Structures of a complete human V-ATPase reveal mechanisms of its assembly. Mol Cell. 2020 Nov 5;80(3):501–511 e3.
   PubMed Web of Science ®Google Scholar
• Kabeya Y, Mizushima N, Ueno T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 2000 Nov 1;19(21):5720–5728.
   PubMed Web of Science ®Google Scholar
• Nair U, Yen W-L, Mari M, et al. A role for Atg8–PE deconjugation in autophagosome biogenesis. Autophagy. 2012;8(5):780–793.
   PubMed Web of Science ®Google Scholar
• Noda T, Klionsky DJ. The quantitative Pho8Delta60 assay of nonspecific autophagy. Methods Enzymol. 2008;451:33–42.
   PubMed Web of Science ®Google Scholar
• Hutchins MU, Klionsky DJ. Vacuolar localization of oligomeric α-mannosidase requires the cytoplasm to vacuole targeting and autophagy pathway components in Saccharomyces cerevisiae. J Biol Chem. 2001;276(23):20491–20498.
   PubMed Web of Science ®Google Scholar
• Kaizuka T, Morishita H, Hama Y, et al. An autophagic flux probe that releases an internal control. Mol Cell. 2016 Nov 17;64(4):835–849.
   PubMed Web of Science ®Google Scholar
• Ronan B, Flamand O, Vescovi L, et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat Chem Biol. 2014 Dec;10(12):1013–1019.
   PubMed Web of Science ®Google Scholar
• Petherick KJ, Conway OJ, Mpamhanga C, et al. Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy. J Biol Chem. 2015 Nov 27;290(48):28726.
   PubMed Web of Science ®Google Scholar
• Hill KJ, Stevens TH. Vma21p is a yeast membrane protein retained in the endoplasmic reticulum by a di-lysine motif and is required for the assembly of the vacuolar H(+)-ATPase complex. Mol Biol Cell. 1994 Sep;5(9):1039–1050.
   PubMed Web of Science ®Google Scholar
• Abu-Remaileh M, Wyant GA, Kim C, et al. Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science. 2017 Nov 10;358(6364):807–813.
   PubMed Web of Science ®Google Scholar
• Sehnal D, Bittrich S, Deshpande M, Svobodová R, Berka K, Bazgier V, Velankar S, Burley S K, Koča J, Rose A S. (2021). Mol* Viewer: modern web app for 3D visualization and analysis of large biomolecular structures. Nucleic Acids Res, 49(W1), W431–W437. https://doi.org/10.1093/nar/gkab314
   PubMed Web of Science ®Google Scholar
• Cannata Serio M, Graham LA, Ashikov A, et al. Mutations in the V-ATPase assembly factor VMA21 cause a congenital disorder of glycosylation with autophagic liver disease. Hepatology. 2020 Dec;72(6):1968–1986.
   PubMed Web of Science ®Google Scholar
• Hughes AL, Gottschling DE. An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast. Nature. 2012 Dec 13;492(7428):261–265.
   PubMed Web of Science ®Google Scholar
• Sambade M, Alba M, Smardon AM, et al. A genomic screen for yeast vacuolar membrane ATPase mutants. Genetics. 2005;170(4):1539–1551.
   PubMed Web of Science ®Google Scholar
• Egan DF, Chun MG, Vamos M, et al. Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates. Mol Cell. 2015 Jul 16;59(2):285–297.
   PubMed Web of Science ®Google Scholar
• Gayle S, Landrette S, Beeharry N, et al. Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood. 2017 Mar 30;129(13):1768–1778.
   PubMed Web of Science ®Google Scholar
• Wells CI, Vasta JD, Corona CR, et al. Quantifying CDK inhibitor selectivity in live cells. Nat Commun. 2020 Jun 2;11(1):2743.
   PubMed Web of Science ®Google Scholar
• Dohmen M, Krieg S, Agalaridis G, et al. AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy. Nat Commun. 2020 Feb 25;11(1):1032.
   PubMed Web of Science ®Google Scholar
• Son SM, Park SJ, Lee H, et al. Leucine signals to mTORC1 via its metabolite acetyl-coenzyme A. Cell Metab. 2019 Jan 8;29(1):192–201 e7.
   PubMed Web of Science ®Google Scholar
• He A, Chen X, Tan M, et al. Acetyl-CoA derived from hepatic peroxisomal beta-oxidation inhibits autophagy and promotes steatosis via mTORC1 activation. Mol Cell. 2020 Jul 2;79(1):30–42 e4.
   PubMed Web of Science ®Google Scholar
• Marino G, Pietrocola F, Eisenberg T, et al. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol Cell. 2014 Mar 6;53(5):710–725.
   PubMed Web of Science ®Google Scholar
• Pattingre S, Tassa A, Qu X, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 2005 Sep 23;122(6):927–939.
   PubMed Web of Science ®Google Scholar
• Rebecca VW, Nicastri MC, McLaughlin N, et al. A unified approach to targeting the lysosome’s degradative and growth signaling roles. Cancer Discov. 2017 Nov;7(11):1266–1283.
   PubMed Web of Science ®Google Scholar
• Lazarus MB, Novotny CJ, Shokat KM, et al. Structure of the human autophagy initiating kinase ULK1 in complex with potent inhibitors. ACS Chem Biol. 2015 Jan 16;10(1):257–261.
   PubMed Web of Science ®Google Scholar
• Li H, Kaminski MS, Li Y, et al. Mutations in linker histone genes HIST1H1 B, C, D, and E; OCT2 (POU2F2); IRF8; and ARID1A underlying the pathogenesis of follicular lymphoma. Blood. 2014 Mar 6;123(10):1487–1498.
   PubMed Web of Science ®Google Scholar
• Ross CW, Ouillette PD, Saddler CM, et al. Comprehensive analysis of copy number and allele status identifies multiple chromosome defects underlying follicular lymphoma pathogenesis. Clin Cancer Res. 2007 Aug 15;13(16):4777–4785.
   PubMed Web of Science ®Google Scholar
• Hu N, Wang F, Sun T, et al. Follicular lymphoma-associated BTK mutations are inactivating resulting in augmented AKT activation. Clin Cancer Res. 2021 Apr 15;27(8):2301–2313.
   PubMed Web of Science ®Google Scholar
• Gueldener U, Heinisch J, Koehler GJ, et al. A second set of loxP marker cassettes for Cre-mediated multiple gene knockouts in budding yeast. Nucleic Acids Res. 2002 Mar 15;30(6):e23.
   PubMed Web of Science ®Google Scholar
• Longtine MS, Mckenzie A III, Demarini DJ, et al. Additional modules for versatile and economical PCR‐based gene deletion and modification in Saccharomyces cerevisiae. Yeast. 1998;14(10):953–961.
   PubMed Web of Science ®Google Scholar
• Feng Y, Ariosa AR, Yang Y, et al. Downregulation of autophagy by Met30-mediated Atg9 ubiquitination. Proc Nat Acad Sci. 2021;118(1):e2005539118.
   PubMed Web of Science ®Google Scholar
• Memisoglu G, Eapen VV, Yang Y, et al. PP2C phosphatases promote autophagy by dephosphorylation of the Atg1 complex. Proc Nat Acad Sci. 2019;116(5):1613–1620.
   PubMed Web of Science ®Google Scholar
• Wen X, Gatica D, Yin Z, et al. The transcription factor Spt4-Spt5 complex regulates the expression of ATG8 and ATG41. Autophagy. 2020 Jul;16(7):1172–1185.
   PubMed Web of Science ®Google Scholar
• Cabrera M, Ungermann C. Chapter thirteen purification and in vitro analysis of yeast vacuoles. Methods Enzymol. 2008;451:177–196.
   PubMed Web of Science ®Google Scholar
• Tomashek JJ, Sonnenburg JL, Artimovich JM, et al. Resolution of subunit interactions and cytoplasmic subcomplexes of the yeast vacuolar proton-translocating ATPase (*). J Biol Chem. 1996;271(17):10397–10404.
   PubMed Web of Science ®Google Scholar
• Morano KA, Klionsky DJ. Differential effects of compartment deacidification on the targeting of membrane and soluble proteins to the vacuole in yeast. J Cell Sci. 1994;107(10):2813–2824.
   PubMedGoogle Scholar
• Bartolommei G, Moncelli MR, Tadini-Buoninsegni F, et al. A method to measure hydrolytic activity of adenosinetriphosphatases (ATPases). PLoS One. 2013;8(3):e58615.
   PubMed Web of Science ®Google Scholar
• Benjamini YHY. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc. 1995;57(1):289–300.
   Google Scholar
• Virtanen P, Gommers R, Oliphant TE, et al. SciPy 1.0: fundamental algorithms for scientific computing in Python. Nat Methods. 2020 Mar;17(3):261–272.
   PubMed Web of Science ®Google Scholar
• Seabold SPJ. statsmodels: econometric and statistical modeling with python. 9th Python in Science Conference; Austin, TX. . 2010.
   Google Scholar
• Hunter JD. Matplotlib: a 2D graphics environment. Comput Sci Eng. 2007;9(3):90–95.
   Web of Science ®Google Scholar
• Klionsky DJ, Cueva R, Yaver DS. Aminopeptidase I of Saccharomyces cerevisiae is localized to the vacuole independent of the secretory pathway. J Cell Biol. 1992 Oct;119(2):287–299.
   PubMed Web of Science ®Google Scholar
• Huang WP, Scott SV, Kim J, et al. The itinerary of a vesicle component, Aut7p/Cvt5p, terminates in the yeast vacuole via the autophagy/Cvt pathways. J Biol Chem. 2000 Feb 25;275(8):5845–5851.
   PubMed Web of Science ®Google Scholar