Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, NIAID, National Institutes of Health, Bethesda, MD 20892, USA.
Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Cell. 2022 Mar 31;185(7):1172-1188.e28. doi: 10.1016/j.cell.2022.02.013. Epub 2022 Mar 17.
Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD.
肠道黏液构成了抵御细菌入侵的第一道防线，同时为支持微生物共生体提供营养。然而，宿主如何控制黏液屏障的完整性和共生关系尚不清楚。我们发现，肠道黏液糖链末端的唾液酸化由 ST6GALNAC1（ST6）所调控，ST6 是一种在杯状细胞中特异性表达的主要唾液酸转移酶，可被微生物病原体相关分子模式诱导。ST6 的表达对于黏液完整性和防止细菌过度蛋白水解降解至关重要。通过对患者中发现的 ST6 突变的糖蛋白质组学分析和生化分析表明，唾液酸化减少会导致黏液蛋白缺陷和先天性炎症性肠病（IBD）。携带患者 ST6 突变的小鼠黏液屏障受损、菌群失调，并且易患肠道炎症。基于我们对 ST6 调控网络的理解，我们发现用唾液酸化的黏蛋白或 Foxo3 抑制剂进行治疗可以改善 IBD。
