USP22 Regulates APL Differentiation Via PML-RARα Stabilization and IFN Repression

Overview

Journal Cell Death Discov

Date 2024 Mar 12

PMID 38467608

Authors

Lisa Kowald

Jens Roedig

Rebekka Karlowitz

Kristina Wagner

Sonja Smith

Thomas Juretschke

Petra Beli

Stefan Muller

Sjoerd J L van Wijk

Affiliations

Soon will be listed here.

Abstract

Ubiquitin-specific peptidase 22 (USP22) is a deubiquitinating enzyme (DUB) that underlies tumorigenicity, proliferation, cell death and differentiation through deubiquitination of histone and non-histone targets. Ubiquitination determines stability, localization and functions of cell fate proteins and controls cell-protective signaling pathways to surveil cell cycle progression. In a variety of carcinomas, lymphomas and leukemias, ubiquitination regulates the tumor-suppressive functions of the promyelocytic leukemia protein (PML), but PML-specific DUBs, DUB-controlled PML ubiquitin sites and the functional consequences of PML (de)ubiquitination remain unclear. Here, we identify USP22 as regulator of PML and the oncogenic acute promyelocytic leukemia (APL) fusion PML-RARα protein stability and identify a destabilizing role of PML residue K394. Additionally, loss of USP22 upregulates interferon (IFN) and IFN-stimulated gene (ISG) expression in APL and induces PML-RARα stabilization and a potentiation of the cell-autonomous sensitivity towards all-trans retinoic acid (ATRA)-mediated differentiation. Our findings imply USP22-dependent surveillance of PML-RARα stability and IFN signaling as important regulator of APL pathogenesis, with implications for viral mimicry, differentiation and cell fate regulation in other leukemia subtypes.

References

Brand P, Lenser T, Hemmerich P . Assembly dynamics of PML nuclear bodies in living cells. PMC Biophys. 2010; 3(1):3. PMC: 2854101. DOI: 10.1186/1757-5036-3-3. View

Nervi C, Ferrara F, Fanelli M, Rippo M, Tomassini B, Ferrucci P . Caspases mediate retinoic acid-induced degradation of the acute promyelocytic leukemia PML/RARalpha fusion protein. Blood. 1998; 92(7):2244-51. View

Schrecengost R, Dean J, Goodwin J, Schiewer M, Urban M, Stanek T . USP22 regulates oncogenic signaling pathways to drive lethal cancer progression. Cancer Res. 2013; 74(1):272-86. PMC: 3947329. DOI: 10.1158/0008-5472.CAN-13-1954. View

Wang Z, Zhu L, Guo T, Wang Y, Yang J . Decreased H2B monoubiquitination and overexpression of ubiquitin-specific protease enzyme 22 in malignant colon carcinoma. Hum Pathol. 2015; 46(7):1006-14. DOI: 10.1016/j.humpath.2015.04.001. View

Akimov V, Barrio-Hernandez I, Hansen S, Hallenborg P, Pedersen A, Bekker-Jensen D . UbiSite approach for comprehensive mapping of lysine and N-terminal ubiquitination sites. Nat Struct Mol Biol. 2018; 25(7):631-640. DOI: 10.1038/s41594-018-0084-y. View

Atanassov B, Mohan R, Lan X, Kuang X, Lu Y, Lin K . ATXN7L3 and ENY2 Coordinate Activity of Multiple H2B Deubiquitinases Important for Cellular Proliferation and Tumor Growth. Mol Cell. 2016; 62(4):558-71. PMC: 4874879. DOI: 10.1016/j.molcel.2016.03.030. View

de The H, Chen Z . Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. Nat Rev Cancer. 2010; 10(11):775-83. DOI: 10.1038/nrc2943. View

Kobayashi T, Iwamoto Y, Takashima K, Isomura A, Kosodo Y, Kawakami K . Deubiquitinating enzymes regulate Hes1 stability and neuronal differentiation. FEBS J. 2015; 282(13):2411-23. DOI: 10.1111/febs.13290. View

Ablain J, Leiva M, Peres L, Fonsart J, Anthony E, de The H . Uncoupling RARA transcriptional activation and degradation clarifies the bases for APL response to therapies. J Exp Med. 2013; 210(4):647-53. PMC: 3620357. DOI: 10.1084/jem.20122337. View

10.

Karlowitz R, Stanifer M, Roedig J, Andrieux G, Bojkova D, Bechtel M . USP22 controls type III interferon signaling and SARS-CoV-2 infection through activation of STING. Cell Death Dis. 2022; 13(8):684. PMC: 9357023. DOI: 10.1038/s41419-022-05124-w. View

11.

Wang Y, Sun Q, Mu N, Sun X, Wang Y, Fan S . The deubiquitinase USP22 regulates PD-L1 degradation in human cancer cells. Cell Commun Signal. 2020; 18(1):112. PMC: 7362500. DOI: 10.1186/s12964-020-00612-y. View

12.

Fanelli M, Minucci S, Gelmetti V, Nervi C, Gambacorti-Passerini C, Pelicci P . Constitutive degradation of PML/RARalpha through the proteasome pathway mediates retinoic acid resistance. Blood. 1999; 93(5):1477-81. View

13.

Chelbi-Alix M, de The H . Herpes virus induced proteasome-dependent degradation of the nuclear bodies-associated PML and Sp100 proteins. Oncogene. 1999; 18(4):935-41. DOI: 10.1038/sj.onc.1202366. View

14.

Lang M, Jegou T, Chung I, Richter K, Munch S, Udvarhelyi A . Three-dimensional organization of promyelocytic leukemia nuclear bodies. J Cell Sci. 2010; 123(Pt 3):392-400. DOI: 10.1242/jcs.053496. View

15.

Liu Y, Yang Y, Xu H, Dong X . Increased expression of ubiquitin-specific protease 22 can promote cancer progression and predict therapy failure in human colorectal cancer. J Gastroenterol Hepatol. 2010; 25(11):1800-5. DOI: 10.1111/j.1440-1746.2010.06352.x. View

16.

Rinfret Robert C, McManus F, Lamoliatte F, Thibault P . Interplay of Ubiquitin-Like Modifiers Following Arsenic Trioxide Treatment. J Proteome Res. 2020; 19(5):1999-2010. DOI: 10.1021/acs.jproteome.9b00807. View

17.

Yuan W, Lee Y, Huang S, Lin Y, Chen T, Chung H . A Cullin3-KLHL20 Ubiquitin ligase-dependent pathway targets PML to potentiate HIF-1 signaling and prostate cancer progression. Cancer Cell. 2011; 20(2):214-28. DOI: 10.1016/j.ccr.2011.07.008. View

18.

Lin Y, Zhong H, Sun B, Peng Y, Lu F, Chen M . USP22 promotes proliferation in renal cell carcinoma by stabilizing survivin. Oncol Lett. 2020; 20(5):246. PMC: 7509511. DOI: 10.3892/ol.2020.12108. View

19.

Wang S, Zhong X, Wang C, Luo H, Lin L, Sun H . USP22 positively modulates ERα action via its deubiquitinase activity in breast cancer. Cell Death Differ. 2020; 27(11):3131-3145. PMC: 7560726. DOI: 10.1038/s41418-020-0568-2. View

20.

Shalem O, Sanjana N, Hartenian E, Shi X, Scott D, Mikkelson T . Genome-scale CRISPR-Cas9 knockout screening in human cells. Science. 2013; 343(6166):84-87. PMC: 4089965. DOI: 10.1126/science.1247005. View