比利时VIB炎症研究中心Geert van Loo及其团队研究发现，A20的两个不同泛素结合结构域介导其抗炎和细胞保护功能。相关论文在线发表于3月16日的《自然-免疫学》。

在本研究中，研究人员设计了Tnfaip3基因靶向的A20突变小鼠，该小鼠在锌指7（ZnF7）和ZnF4泛素结合域具有失活突变，这表明与多泛素因子结合对于A20抑制炎症性疾病至关重要。

研究人员证明，ZnF7功能性结构域是招募A20到肿瘤坏死因子受体1（TNFR1）信号复合物和抑制炎症信号和细胞死亡所必需的。ZnF4和ZnF7的联合失活导致A20缺陷小鼠产后致死和严重的多器官炎症。组织特异性表达突变体A20进一步揭示了泛素结合在髓样和肠上皮细胞中的关键作用。

总体而言，这些结果表明A20的抗炎和细胞保护功能在很大程度上取决于其泛素结合特性。

据了解，泛素化调节蛋白质的稳定性并调控信号复合物的组成。A20是炎症信号的负调控因子，但其涉及的分子机制尚不明确。

附：英文原文

Title: Two distinct ubiquitin-binding motifs in A20 mediate its anti-inflammatory and cell-protective activities

Author: Arne Martens, Dario Priem, Esther Hoste, Jessica Vetters, Sofie Rennen, Leen Catrysse, Sofie Voet, Laura Deelen, Mozes Sze, Hanna Vikkula, Karolina Slowicka, Tino Hochepied, Kalliopi Iliaki, Andy Wullaert, Sophie Janssens, Mohamed Lamkanfi, Rudi Beyaert, Marietta Armaka, Mathieu J. M. Bertrand, Geert van Loo

Issue&Volume: 2020-03-16

Abstract: Protein ubiquitination regulates protein stability and modulates the composition of signaling complexes. A20 is a negative regulator of inflammatory signaling, but the molecular mechanisms involved are ill understood. Here, we generated Tnfaip3 gene-targeted A20 mutant mice bearing inactivating mutations in the zinc finger 7 (ZnF7) and ZnF4 ubiquitin-binding domains, revealing that binding to polyubiquitin is essential for A20 to suppress inflammatory disease. We demonstrate that a functional ZnF7 domain was required for recruiting A20 to the tumor necrosis factor receptor 1 (TNFR1) signaling complex and to suppress inflammatory signaling and cell death. The combined inactivation of ZnF4 and ZnF7 phenocopied the postnatal lethality and severe multiorgan inflammation of A20-deficient mice. Conditional tissue-specific expression of mutant A20 further revealed the key role of ubiquitin-binding in myeloid and intestinal epithelial cells. Collectively, these results demonstrate that the anti-inflammatory and cytoprotective functions of A20 are largely dependent on its ubiquitin-binding properties.

DOI: 10.1038/s41590-020-0621-9

Source: https://www.nature.com/articles/s41590-020-0621-9