USP40 deubiquitinates HINT1 and stabilizes p53 in podocyte damage
USP40 deubiquitinates HINT1 and stabilizes p53 in podocyte damage
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DOI：
10.1016/j.bbrc.2022.05.043
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发表时间：
2022-05-20
影响因子：
3.1
通讯作者：
Yan, Kunimasa
中科院分区：
文献类型：
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作者：
Takahashi, Shohei;Fukuhara, Daisuke;Yan, Kunimasa
足细胞损伤是导致局灶节段性肾小球硬化症（FSGS）的主要病理损伤。被细胞应激损伤的足细胞经历肥大以补偿足细胞减少。已知p53诱导的细胞周期蛋白依赖性激酶抑制剂可导致足细胞肥大，但其确切机制仍有待进一步研究。在这项研究中，我们发现泛素特异性蛋白酶40（USP 40）是一种新的p53调节剂。虽然在本研究中建立的USP 40敲除小鼠显示没有异常的肾脏表型，但中间丝巢蛋白在肾小球中上调，并且与USP 40结合并共定位。我们还发现USP 40去泛素化组氨酸三联体核苷酸结合蛋白1（HINT 1），p53的诱导剂。在足细胞中的USP 40基因敲低实验显示HINT 1和p53蛋白表达减少。最后，在小鼠FSGS的肾小球足细胞中，HINT 1的上调发生在蛋白尿之前，随后USP 40、p53和Nestin的上调。总之，USP 40结合巢蛋白去泛素化HINT 1，并因此上调p53。这些结果为FSGS足细胞肥大的病理机制提供了新的见解。(c)2022爱思唯尔公司All rights reserved.
Podocyte damage is a major pathological lesion leading to focal segmental glomerulosclerosis (FSGS). Podocytes damaged by cellular stress undergo hypertrophy to compensate for podocytopenia. It is known that cyclin-dependent kinase inhibitors induced by p53 ensure podocytes hypertrophy; however, its precise mechanism remains to be further investigated. In this study, we found that ubiquitin specific protease 40 (USP40) is a novel regulator of p53. Although USP40 knockout mice established in the present study revealed no abnormal kidney phenotype, intermediate filament Nestin was upregulated in the glomeruli, and was bound to and colocalized with USP40. We also found that USP40 deubiquitinated histidine triad nucleotide-binding protein 1 (HINT1), an inducer of p53. Gene knockdown experiments of USP40 in cultured podocytes revealed the reduction of HINT1 and p53 protein expression. Finally, in glomerular podocytes of mouse FSGS, upregulation of HINT1 occurred in advance of the proteinuria, which was followed by upregulation of USP40, p53 and Nestin. In conclusion, USP40 bound to Nestin deubiquitinates HINT1, and in consequence upregulates p53. These results provide additional insight into the pathological mechanism of podocyte hypertrophy in FSGS.(c) 2022 Elsevier Inc. All rights reserved.