MAD2B-mediated cell cycle reentry of podocytes is involved in the pathogenesis of FSGS.

Dian Bao, Hua Su, Chun-Tao Lei, Hui Tang, Chen Ye, Wei Xiong, Fang-Fang He, Ji-Hong Lin, Hans-Peter Hammes, Chun Zhang

International journal of biological sciences 2021

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Rationale: Focal segmental glomerulosclerosis (FSGS) is characterized by the dysfunction of "post-mitotic" podocytes. The reentry of podocytes in the cell cycle will ultimately result in cell death. Mitotic arrest deficient 2-like protein 2 (MAD2B), an inhibitor of anaphase-promoting complex (APC)/cyclosome, precisely controls the metaphase to anaphase transition and ordered cell cycle progression. However, the role of MAD2B in FSGS podocyte injury remains unknown. Methods: To explore MAD2B function in podocyte cell cycle reentry, we used conditional mutant mice lacking MAD2B selectively in podocytes in ADR-induced FSGS murine model. Additionally, KU-55933, a specific inhibitor of ataxia-telangiectasia mutated (ATM) was utilized in vivo and in vitro to explore the role of ATM in regulating MAD2B. Results: The expression of MAD2B in podocytes was dramatically increased in patients with FSGS and ADR-treated mice along with podocyte cell cycle reentry. Podocyte-specific knockout of MAD2B effectively attenuated proteinuria, podocyte injury, and prevented the aberrant cell cycle reentry. By bioinformatics analysis we revealed that ATM kinase is a key upstream regulator of MAD2B. Furthermore, inhibition of ATM kinase abolished MAD2B-driven cell cycle reentry and alleviated podocyte impairment in FSGS murine model. In vitro studies by site-directed mutagenesis and immunoprecipitation we revealed ATM phosphorylated MAD2B and consequently hampered the ubiquitination of MAD2B in a phosphorylation-dependent manner. Conclusions: ATM kinase-MAD2B axis importantly contributes to the cell cycle reentry of podocytes, which is a novel pathogenic mechanism of FSGS, and may shed light on the development of its therapeutic approaches. © The author(s).

Citation

Dian Bao, Hua Su, Chun-Tao Lei, Hui Tang, Chen Ye, Wei Xiong, Fang-Fang He, Ji-Hong Lin, Hans-Peter Hammes, Chun Zhang. MAD2B-mediated cell cycle reentry of podocytes is involved in the pathogenesis of FSGS. International journal of biological sciences. 2021;17(15):4396-4408