美国麻省大学医学院Katherine A. Fitzgerald、Liraz Shmuel-Galia等研究人员合作发现，肠道生态失调通过促进骨髓细胞中先天免疫接头蛋白STING的泛素化和积累来加剧结肠炎。该研究于2021年5月28日在线发表于国际一流学术期刊《免疫》。

研究人员报道了STING在肠道炎症中的功能作用。STING表达增加是结肠炎小鼠和炎症性肠病患者的一个特征。携带使STING组成性活跃的等位基因小鼠表现出自发性结肠炎和肠道生态失调，以及进行性慢性肠道炎症和纤维化。骨髓嵌合体实验表明，肠道巨噬细胞和单核细胞中的STING积累是炎症的最初驱动因素。革兰氏阴性菌的消耗阻止了这些细胞中STING的积累并减轻了肠道炎症。STING积累发生在蛋白质而不是转录水平，这提示翻译后的稳定性调节。

研究人员发现STING在骨髓细胞中泛素化，并且这种K63连接的泛素化可以由细菌产物引起，包括环二GMP。这些研究结果表明存在一个正反馈循环，其中肠道生态失调会导致STING在肠道髓系细胞中的积累，从而导致肠道炎症。

据悉，cGAS-STING DNA传感途径的改变影响肠道稳态。

附：英文原文

Title: Dysbiosis exacerbates colitis by promoting ubiquitination and accumulation of the innate immune adaptor STING in myeloid cells

Author: Liraz Shmuel-Galia, Fiachra Humphries, Xuqiu Lei, Simona Ceglia, Ruth Wilson, Zhaozhao Jiang, Natalia Ketelut-Carneiro, Sage E. Foley, Susanne Pechhold, JeanMarie Houghton, Khaja Muneeruddin, Scott A. Shaffer, Beth A. McCormick, Andrea Reboldi, Doyle Ward, Ann Marshak-Rothstein, Katherine A. Fitzgerald

Issue&Volume: 2021-05-28

Abstract: Alterations in the cGAS-STING DNA-sensing pathway affect intestinal homeostasis. Wesought to delineate the functional role of STING in intestinal inflammation. IncreasedSTING expression was a feature of intestinal inflammation in mice with colitis andin humans afflicted with inflammatory bowel disease. Mice bearing an allele renderingSTING constitutively active exhibited spontaneous colitis and dysbiosis, as well asprogressive chronic intestinal inflammation and fibrosis. Bone marrow chimera experimentsrevealed STING accumulation in intestinal macrophages and monocytes as the initialdriver of inflammation. Depletion of Gram-negative bacteria prevented STING accumulationin these cells and alleviated intestinal inflammation. STING accumulation occurredat the protein rather than transcript level, suggesting post-translational stabilization.We found that STING was ubiquitinated in myeloid cells, and this K63-linked ubiquitinationcould be elicited by bacterial products, including cyclic di-GMP. Our findings suggesta positive feedback loop wherein dysbiosis foments the accumulation of STING in intestinalmyeloid cells, driving intestinal inflammation.

DOI: 10.1016/j.immuni.2021.05.008

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00214-4