MAD2B-mediated cell cycle reentry of podocytes is involved in the pathogenesis of FSGS.
MAD2B-mediated cell cycle reentry of podocytes is involved in the pathogenesis of FSGS.
复制标题
MAD2B 介导的足细胞细胞周期折返参与 FSGS 的发病机制。
DOI：
10.7150/ijbs.62238
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发表时间：
2021
影响因子：
9.2
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Bao D;Su H;Lei CT;Tang H;Ye C;Xiong W;He FF;Lin JH;Hammes HP;Zhang C
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.
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影响因子：
6.4
作者：
Rimkus, Caroline;Friederichs, Jan;Janssen, Klaus-Peter
通讯作者：
Janssen, Klaus-Peter
影响因子：
6.1
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Muehldorfer, Johanna;Pfister, Eva;Daniel, Christoph
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Daniel, Christoph
影响因子：
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Xiao, Wei
影响因子：
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作者：
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通讯作者：
Zhang C
影响因子：
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作者：
Brinkkoetter, Paul T.;Olivier, Paul;Shankland, Stuart J.
通讯作者：
Shankland, Stuart J.