USP13 Regulates Cell Senescence Through Mediating MDM2 Stability

Overview

Journal Life Sci

Publisher Elsevier

Specialties Biochemistry
Biology
Physiology

Date 2023 Aug 27

PMID 37634814

Authors

Jinshan He

Boina Baoyinna

Sarah J Taleb

Jing Zhao

Yutong Zhao

Affiliations

Soon will be listed here.

Abstract

Aims: Lung aging results in altered lung function, reduced lung remodeling and regenerative capacity, and increased susceptibility to acute and chronic lung diseases. The molecular and physiological underlying mechanisms of lung aging remain unclear. Mounting evidence suggests that deubiquitinating enzymes (DUBs) play a critical role in tissue aging and diseases through regulation of cellular signaling pathways. Here we investigate the role of Ubiquitin-Specific Protease 13 (USP13) in cell senescence and lung aging and its underlying mechanisms.

Main Methods: Protein levels of USP13 and MDM2 in lung tissues from aged and young mice were compared. Gene silencing and overexpression of USP13 in human cell lines were performed. MDM2 levels were examined by Quantitative Real-Time PCR and Western blotting analysis. The cell senescence levels of human cells were checked by the β-galactosidase staining.

Key Findings: Lung tissues from aged mice showed higher levels of USP13 compared to younger mice. We found a negative correlation between USP13 and MDM2 expression in lung tissues of aged mice. The increased protein levels of MDM2 were detected in lung tissues of USP13 deficient mice. Furthermore, overexpression of USP13 promoted cell senescence. Knockdown of USP13 increased MDM2 levels in lung cells, while overexpression of USP13 reduced it. The degradation of MDM2 caused by USP13 was prevented by the proteasome inhibitor MG132. Furthermore, we showed that USP13 targeted and reduced K63-linked polyubiquitination of MDM2. These results demonstrate that USP13 is involved in the aging signaling pathway in lungs through regulation of MDM2.

Citing Articles

Matrix-free human lung organoids derived from induced pluripotent stem cells to model lung injury.

Budeus B, Kroepel C, Stasch L, Klein D Stem Cell Res Ther. 2024; 15(1):468.

PMID: 39696649 PMC: 11657174. DOI: 10.1186/s13287-024-04106-3.

The mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation.

Yang Y, Wang B, Dong H, Lin H, Ho M, Hu K Proc Natl Acad Sci U S A. 2024; 121(44):e2401218121.

PMID: 39436667 PMC: 11536080. DOI: 10.1073/pnas.2401218121.

Molecular Regulation of Transforming Growth Factor-β1-induced Thioredoxin-interacting Protein Ubiquitination and Proteasomal Degradation in Lung Fibroblasts: Implication in Pulmonary Fibrosis.

Taleb S, Ye Q, Baoyinna B, Dedad M, Pisini D, Parinandi N J Respir Biol Transl Med. 2024; 1(1).

PMID: 38529321 PMC: 10962057. DOI: 10.35534/jrbtm.2024.10002.

Friend or foe? Reciprocal regulation between E3 ubiquitin ligases and deubiquitinases.

Bolhuis D, Emanuele M, Brown N Biochem Soc Trans. 2024; 52(1):241-267.

PMID: 38414432 PMC: 11349938. DOI: 10.1042/BST20230454.

References

Komander D, Clague M, Urbe S . Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol. 2009; 10(8):550-63. DOI: 10.1038/nrm2731. View

Zhang J, Zhang P, Wei Y, Piao H, Wang W, Maddika S . Deubiquitylation and stabilization of PTEN by USP13. Nat Cell Biol. 2013; 15(12):1486-1494. PMC: 3951854. DOI: 10.1038/ncb2874. View

Li L, Zhao D, Wei H, Yao L, Dang Y, Amjad A . REGγ deficiency promotes premature aging via the casein kinase 1 pathway. Proc Natl Acad Sci U S A. 2013; 110(27):11005-10. PMC: 3703992. DOI: 10.1073/pnas.1308497110. View

Liu J, Xia H, Kim M, Xu L, Li Y, Zhang L . Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell. 2011; 147(1):223-34. PMC: 3441147. DOI: 10.1016/j.cell.2011.08.037. View

Marine J, Lozano G . Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ. 2009; 17(1):93-102. DOI: 10.1038/cdd.2009.68. View

Deng H, Ikeda A, Cui H, Bartlett J, Suzuki M . MDM2-Mediated p21 Proteasomal Degradation Promotes Fluoride Toxicity in Ameloblasts. Cells. 2019; 8(5). PMC: 6562432. DOI: 10.3390/cells8050436. View

Hernandez-Monge J, Martinez-Sanchez M, Rousset-Roman A, Medina-Medina I, Olivares-Illana V . MDM2 regulates RB levels during genotoxic stress. EMBO Rep. 2020; 22(1):e50615. PMC: 7788445. DOI: 10.15252/embr.202050615. View

Jin Y, Lee H, Zeng S, Dai M, Lu H . MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation. EMBO J. 2003; 22(23):6365-77. PMC: 291841. DOI: 10.1093/emboj/cdg600. View

Ma J, Zhang Y, Wang L, Sun Q, Zhang H, Li J . K63 Ubiquitination of P21 Can Facilitate Pellino-1 in the Context of Chronic Obstructive Pulmonary Disease and Lung Cellular Senescence. Cells. 2022; 11(19). PMC: 9563803. DOI: 10.3390/cells11193115. View

10.

Zhao K, Yang Y, Zhang G, Wang C, Wang D, Wu M . Regulation of the Mdm2-p53 pathway by the ubiquitin E3 ligase MARCH7. EMBO Rep. 2018; 19(2):305-319. PMC: 5797962. DOI: 10.15252/embr.201744465. View

11.

Zhao G, Wang H, Xu C, Wang P, Chen J, Wang P . SIRT6 delays cellular senescence by promoting p27Kip1 ubiquitin-proteasome degradation. Aging (Albany NY). 2016; 8(10):2308-2323. PMC: 5115890. DOI: 10.18632/aging.101038. View

12.

Liu H, Zhao Z, Wu T, Zhang Q, Lu F, Gu J . Inhibition of autophagy-dependent pyroptosis attenuates cerebral ischaemia/reperfusion injury. J Cell Mol Med. 2021; 25(11):5060-5069. PMC: 8178262. DOI: 10.1111/jcmm.16483. View

13.

Mayo L, Dixon J, Durden D, Tonks N, Donner D . PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J Biol Chem. 2001; 277(7):5484-9. DOI: 10.1074/jbc.M108302200. View

14.

Liu X, Balaraman K, Lynch C, Hebron M, Wolf C, Moussa C . Novel Ubiquitin Specific Protease-13 Inhibitors Alleviate Neurodegenerative Pathology. Metabolites. 2021; 11(9). PMC: 8467576. DOI: 10.3390/metabo11090622. View

15.

Xu C, Fan C, Wang X . Regulation of Mdm2 protein stability and the p53 response by NEDD4-1 E3 ligase. Oncogene. 2014; 34(3):281-9. DOI: 10.1038/onc.2013.557. View

16.

Zhang Z, Wang H, Li M, Agrawal S, Chen X, Zhang R . MDM2 is a negative regulator of p21WAF1/CIP1, independent of p53. J Biol Chem. 2004; 279(16):16000-6. DOI: 10.1074/jbc.M312264200. View

17.

Gannon H, Donehower L, Lyle S, Jones S . Mdm2-p53 signaling regulates epidermal stem cell senescence and premature aging phenotypes in mouse skin. Dev Biol. 2011; 353(1):1-9. PMC: 3075331. DOI: 10.1016/j.ydbio.2011.02.007. View

18.

Sun H, Zhang Q, Jing Y, Zhang M, Wang H, Cai Z . USP13 negatively regulates antiviral responses by deubiquitinating STING. Nat Commun. 2017; 8:15534. PMC: 5457515. DOI: 10.1038/ncomms15534. View

19.

Silva G, Finley D, Vogel C . K63 polyubiquitination is a new modulator of the oxidative stress response. Nat Struct Mol Biol. 2015; 22(2):116-23. PMC: 4318705. DOI: 10.1038/nsmb.2955. View

20.

Angelidis I, Simon L, Fernandez I, Strunz M, Mayr C, Greiffo F . An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics. Nat Commun. 2019; 10(1):963. PMC: 6393476. DOI: 10.1038/s41467-019-08831-9. View