The E3 ubiquitin ligase TRIM31 plays a critical role in hypertensive nephropathy by promoting proteasomal degradation of MAP3K7 in the TGF-beta 1 signaling pathway
The E3 ubiquitin ligase TRIM31 plays a critical role in hypertensive nephropathy by promoting proteasomal degradation of MAP3K7 in the TGF-beta 1 signaling pathway
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E3 泛素连接酶 TRIM31 通过促进 TGF-β1 信号通路中 MAP3K7 的蛋白酶体降解，在高血压肾病中发挥关键作用。
DOI：
10.1038/s41418-021-00874-0
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发表时间：
2021-09-28
影响因子：
12.4
通讯作者：
Zhang，Yun
中科院分区：
文献类型：
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作者：
Zhang，Jie;Cao，Lei;Zhang，Yun
肾纤维化和炎症是高血压肾病（HRD）发生和发展的关键。然而，其诱导的信号转导机制知之甚少，三重基序包含蛋白31（TRIM 31），E3泛素连接酶，在HRD中的作用仍然不清楚。本研究旨在阐明TRIM 31在HRD发病机制中的作用，发现TRIM 31的作用靶点，并探讨其作用机制。收集人HRD肾脏病理标本，建立血管紧张素II（AngII）诱导的HRD小鼠模型。我们发现TRIM 31在人类和小鼠HRD肾组织中均显著减少。因此构建了TRIM 31 −/−小鼠，并且与TRIM 31 +/+小鼠相比，在慢性AngII输注后，TRIM 31 −/−小鼠显示出显著加重的高血压诱导的肾功能不全、纤维化和炎症。相比之下，通过将腺相关病毒（AAV）9注射到C57 BL/6 J小鼠中过表达TRIM 31，相对于AAV对照小鼠，显著改善AngII诱导的HRD中的肾功能障碍、纤维化和炎症反应。TRIM 31与丝裂原活化蛋白激酶7（MAPK 3 K7）上的赖氨酸72相互作用并催化其K48连接的多泛素化，随后通过蛋白酶体降解MAPK 3 K7，进一步负调控TGF-β1介导的Smad和MAPK/NF-κB信号通路。总之，本研究首次证明TRIM 31通过促进MAP 3 K7 K48连接的多聚泛素化和抑制TGF-β1信号通路在AngII诱导的HRD中起重要调节作用。
Renal fibrosis and inflammation are critical for the initiation and progression of hypertensive renal disease (HRD). However, the signaling mechanisms underlying their induction are poorly understood, and the role of tripartite motif-containing protein 31 (TRIM31), an E3 ubiquitin ligase, in HRD remains unclear. This study aimed to elucidate the role of TRIM31 in the pathogenesis of HRD, discover targets of TRIM31, and explore the underlying mechanisms. Pathological specimens of human HRD kidney were collected and an angiotensin II (AngII)-induced HRD mouse model was developed. We found that TRIM31 was markedly reduced in both human and mouse HRD renal tissues. A TRIM31−/−mice was thus constructed and showed significantly aggravated hypertension-induced renal dysfunction, fibrosis, and inflammation, following chronic AngII infusion compared with TRIM31+/+mice. In contrast, overexpression of TRIM31 by injecting adeno-associated virus (AAV) 9 into C57BL/6J mice markedly ameliorated renal dysfunction, fibrotic and inflammatory response in AngII-induced HRD relative to AAV-control mice. Mechanistically, TRIM31 interacted with and catalyzed the K48-linked polyubiquitination of lysine 72 on Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), followed by the proteasomal degradation of MAP3K7, which further negatively regulated TGF-β1-mediated Smad and MAPK/NF-κB signaling pathways. In conclusion, this study has demonstrated for the first time that TRIM31 serves as an important regulator in AngII-induced HRD by promoting MAP3K7 K48-linked polyubiquitination and inhibiting the TGF-β1 signaling pathway.