S100A16 promotes acute kidney injury by activating HRD1-induced ubiquitination and degradation of GSK3β and CK1α.
S100A16 promotes acute kidney injury by activating HRD1-induced ubiquitination and degradation of GSK3β and CK1α.
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S100A16 通过激活 HRD1 诱导的泛素化和 GSK3β 和 CK1α 的降解来促进急性肾损伤
DOI：
10.1007/s00018-022-04213-5
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发表时间：
2022-03-12
期刊：
影响因子：
--
通讯作者：
Liang X
中科院分区：
文献类型：
--
作者：
Sun Y;Fan Y;Wang Z;Li M;Su D;Liu Y;Liang X
急性肾损伤（acute kidney injury，阿基）的发病机制与包括Wnt/β-catenin信号通路在内的多种信号通路的激活有关。然而，阿基期间肾间质成纤维细胞中Wnt/β-catenin通路激活的机制尚不清楚。S100钙结合蛋白A16（S100 A16）是钙结合蛋白S100家族的一个新成员，是一种多功能的信号转导因子，与肿瘤、糖脂代谢紊乱、慢性肾脏病等多种疾病密切相关。我们研究了S100 A16在阿基期间Wnt/β-catenin通路激活中的潜在参与，通过将野生型（WT）和S100 A16基因敲除的AKI小鼠与野生型（WT）和S100 A16基因敲除的AKI小鼠进行比较，（S100 A16 +/-）小鼠对缺血-再灌注损伤（IRI）的耐受性，并揭示在该模型中S100 A16上调，其中S100 A16基因敲除抑制了Wnt/β-catenin信号通路的激活，恢复了下游肝细胞生长因子（HGF）的表达。我们还发现S100 A16在体内血小板衍生生长因子受体β（PDGFRβ）阳性的肾成纤维细胞中高表达。一致地，在大鼠肾间质成纤维细胞（NRK-49 F细胞）中，缺氧/复氧和S100 A16过表达均加剧成纤维细胞凋亡并抑制HGF分泌;而S100 A16敲除或Wnt/β-catenin通路抑制剂ICG-001逆转了这些变化。在机制上，我们发现S100 A16通过泛素化和降解β-连环蛋白复合体成员糖原合成酶激酶3β（GSK 3 β）和酪蛋白激酶1α（CK 1 α），由E3泛素连接酶，HMG-CoA还原酶降解蛋白1（HRD 1）介导，促进Wnt/β-连环蛋白信号激活。我们的研究确定S100 A16是阿基中Wnt/β-catenin信号通路激活的关键调节因子。在线版本包含补充材料，可通过10.1007/s 00018 -022-04213-5获得。
The pathogenesis of acute kidney injury (AKI) is associated with the activation of multiple signaling pathways, including Wnt/β-catenin signaling. However, the mechanism of Wnt/β-catenin pathway activation in renal interstitial fibroblasts during AKI is unclear. S100 calcium-binding protein A16 (S100A16), a new member of calcium-binding protein S100 family, is a multi-functional signaling factor involved in various pathogenies, including tumors, glycolipid metabolism disorder, and chronic kidney disease (CKD). We investigated the potential participation of S100A16 in Wnt/β-catenin pathway activation during AKI by subjecting wild-type (WT) and S100A16 knockout (S100A16+/−) mice to the ischemia–reperfusion injury (IRI), and revealed S100A16 upregulation in this model, in which knockout of S100A16 impeded the Wnt/β-catenin signaling pathway activation and recovered the expression of downstream hepatocyte growth factor (HGF). We also found that S100A16 was highly expressed in Platelet-derived growth factor receptor beta (PDGFRβ) positive renal fibroblasts in vivo. Consistently, in rat renal interstitial fibroblasts (NRK-49F cells), both hypoxia/reoxygenation and S100A16 overexpression exacerbated fibroblasts apoptosis and inhibited HGF secretion; whereas S100A16 knockdown or Wnt/β-catenin pathway inhibitor ICG-001 reversed these changes. Mechanistically, we showed that S100A16 promoted Wnt/β-catenin signaling activation via the ubiquitylation and degradation of β-catenin complex members, glycogen synthase kinase 3β (GSK3β) and casein kinase 1α (CK1α), mediated by E3 ubiquitin ligase, the HMG-CoA reductase degradation protein 1 (HRD1). Our study identified the S100A16 as a key regulator in the activation of Wnt/β-catenin signaling pathway in AKI. The online version contains supplementary material available at 10.1007/s00018-022-04213-5.
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