Ubiquitin Specific Protease 21 Is Dispensable for Normal Development, Hematopoiesis and Lymphocyte Differentiation
Open accessAbstract
USP21 is a ubiquitin specific protease that catalyzes protein deubiquitination, however the identification of its physiological substrates remains challenging. USP21 is known to deubiquitinate transcription factor GATA3 and death-domain kinase RIPK1 in vitro, however the in vivo settings where this regulation plays a biologically significant role remain unknown. In order to determine whether USP21 is an essential and non-redundant regulator of GATA3 or RIPK1 activity in vivo, we characterized Usp21-deficient mice, focusing on mouse viability and development, hematopoietic stem cell function, and lymphocyte differentiation. The Usp21-knockout mice were found to be viable and fertile, with no significant dysmorphology, in contrast to the GATA3 and RIPK1 knockout lines that exhibit embryonic or perinatal lethality. Loss of USP21 also had no effect on hematopoietic stem cell function, lymphocyte development, or the responses of antigen presenting cells to TLR and TNFR stimulation. GATA3 levels in hematopoietic stem cells or T lymphocytes remained unchanged. We observed that aged Usp21-knockout mice exhibited spontaneous T cell activation, however this was not linked to altered GATA3 levels in the affected cells. The contrast in the phenotype of the Usp21-knockout line with the previously characterized GATA3 and RIPK1 knockout mice strongly indicates that USP21 is redundant for the regulation of GATA3 and RIPK1 activity during mouse development, in hematopoietic stem cells, and in lymphocyte differentiation. The Usp21-deficient mouse line characterized in this study may serve as a useful tool for the future characterization of USP21 physiological functions.
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USP21 is expected to be a viable therapeutic target in PDAC, either as monotherapy or in combination with inhibitors targeting KRAS mutation.
“Therefore, USP21 is expected to be a viable therapeutic target in PDAC, either as monotherapy or in combination with inhibitors targeting KRAS mutation [51, 52].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [52]
USP21 overexpression also upregulates mTOR-related signaling pathways.
“USP21 overexpression also upregulates mTOR-related signaling pathways.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [52]
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Targeting KRAS mutant cancers: from druggable therapy to drug resistance
Zhu, C., Guan, X., Zhang, X., Luan, X., Song, Z., Cheng, X., Zhang, W., & Qin, J.-J. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01629-2 · Cited by 231 · see citing works
- Authors
- Pannu, J., Belle, J. I., Förster, M., Duerr, C. U., Shen, S., Kane, L., Harcourt, K., Fritz, J. H., Clare, S., & Nijnik, A.
- Affiliations
- McGill University (CA)
- Wellcome Sanger Institute (GB)
- Corresponding author
- Nijnik, Anastasia
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-02-13
- Volume
- 10
- Issue
- 2
- Pages
- e0117304
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4332479
- OpenAlex
- W1997739317
- Cited by
- 37
- References
- 39
- Citations by year
- 2026: 4 · 2023: 3 · 2022: 2 · 2021: 7 · 2020: 4 · 2019: 5 · 2018: 1 · 2017: 4 · 2016: 4 · 2015: 2
- FWCI
- 1.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship@McGill (McGill) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Funders
- McGill University
- Wellcome Trust (098051)
- Deutsche Forschungsgemeinschaft (900/1‐1, DFG FO 900/1-1)
- Deutsche Akademie der Naturforscher Leopoldina - Nationale Akademie der Wissenschaften
- Canadian Institutes of Health Research (Tier 2)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- USP21, ubiquitin-specific protease, deubiquitination, GATA3, RIPK1, hematopoietic stem cells, lymphocyte differentiation, T cell activation, embryonic lethality, ubiquitination
- MeSH terms
- Animals, Cell Differentiation, Dendritic Cells, Hematopoiesis, Hematopoietic Stem Cells, Lymphocyte Activation, Lymphocytes, Macrophages, T-Lymphocytes, Immunophenotyping, Receptors, Tumor Necrosis Factor, Mice, Knockout, Gene Targeting, Gene Order, Ubiquitin Thiolesterase, GATA3 Transcription Factor, Toll-Like Receptors, Mice, Genetic Loci
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