USP22 regulates APL differentiation via PML-RARα stabilization and IFN repression
In: Cell Death Discovery, Jg. 10 (2024), Heft 1, S. 1-11
Online
academicJournal
Zugriff:
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.
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USP22 regulates APL differentiation via PML-RARα stabilization and IFN repression
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Autor/in / Beteiligte Person: | Kowald, Lisa ; Roedig, Jens ; Karlowitz, Rebekka ; Wagner, Kristina ; Smith, Sonja ; Juretschke, Thomas ; Beli, Petra ; Müller, Stefan ; Sjoerd J. L. van Wijk |
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Zeitschrift: | Cell Death Discovery, Jg. 10 (2024), Heft 1, S. 1-11 |
Veröffentlichung: | Nature Publishing Group, 2024 |
Medientyp: | academicJournal |
ISSN: | 2058-7716 (print) |
DOI: | 10.1038/s41420-024-01894-8 |
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