Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C.
Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C.
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DOI：
10.1016/j.immuni.2022.03.009
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发表时间：
2022-04-12
期刊：
影响因子：
32.4
通讯作者：
Ruan, Hai-Bin
中科院分区：
文献类型：
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作者：
Zhao, Ming;Ren, Kaiqun;Xiong, Xiwen;Xin, Yue;Zou, Yujie;Maynard, Jason C.;Kim, Angela;Battist, Alexander P.;Koneripalli, Navya;Wang, Yusu;Chen, Qianyue;Xin, Ruyue;Yang, Chenyan;Huang, Rong;Yu, Jiahui;Huang, Zan;Zhang, Zengdi;Wang, Haiguang;Wang, Daoyuan;Xiao, Yihui;Salgado, Oscar C.;Jarjour, Nicholas N.;Hogquist, Kristin A.;Revelo, Xavier S.;Burlingame, Alma L.;Gao, Xiang;von Moltke, Jakob;Lin, Zhaoyu;Ruan, Hai-Bin
上皮是黏膜屏障和宿主免疫的重要组成部分。肠道上皮细胞感染蠕虫后，分泌白介素25(IL-25)和白介素33(IL-33)等“警报”细胞因子，启动驱虫和耐受的2型免疫反应。然而，目前尚不清楚蠕虫感染和由此产生的细胞因子环境是如何推动上皮重塑和协调警蛋白分泌的。在此，我们报道了上皮性O-连接N-乙酰氨基葡萄糖(O-GlcNAc)蛋白在蠕虫感染时被诱导的修饰。O-GlcNAc转移酶通过修饰和激活转录因子STAT6，在丛生细胞分化和IL-25产生中促进谱系定义的Pou2f3的转录。同时，STAT6 O-GlcN酰化激活了Gsdmc家族基因的表达。GSDMC形成的膜孔促进IL-33的非常规分泌。GSDMC介导的IL-33分泌是有效的抗蠕虫免疫所必需的，也是诱导肠道炎症的原因之一。蛋白质O-GlcN酰化可用于未来治疗与2型炎症相关的人类疾病。STAT6是抗蠕虫免疫所必需的，但目前尚不清楚STAT6的活性是如何被微调以协调“警报”细胞因子反应的。赵等人揭示，O-GlcNAc修饰允许STAT6驱动产生IL-25的簇状细胞的分化，并通过GSDMC膜孔促进非常规IL-33的分泌。
The epithelium is an integral component of mucosal barrier and host immunity. Following helminth infection, the intestinal epithelial cells secrete “alarmin” cytokines, such as interleukin-25 (IL-25) and IL-33, to initiate the type 2 immune responses for helminth expulsion and tolerance. However, it is unknown how helminth infection and the resulting cytokine milieu drive epithelial remodeling and orchestrate alarmin secretion. Here we report that, epithelial O-linked N-Acetylglucosamine (O-GlcNAc) protein modification was induced upon helminth infections. By modifying and activating the transcription factor STAT6, O-GlcNAc transferase promoted the transcription of lineage-defining Pou2f3 in tuft cell differentiation and IL-25 production. Meanwhile, STAT6 O-GlcNAcylation activated the expression of Gsdmc family genes. The membrane pore formed by GSDMC facilitated the unconventional secretion of IL-33. GSDMC-mediated IL-33 secretion was indispensable for effective antihelminth immunity and contributed to induced intestinal inflammation. Protein O-GlcNAcylation can be harnessed for future treatment of type 2 inflammation-associated human diseases. STAT6 is requisite for anti-helminth immunity, but it is presently unclear how STAT6 activity is finetuned to orchestrate “alarmin” cytokine responses. Zhao et al reveal that O-GlcNAc modification allows STAT6 to drive the differentiation of IL-25-producing tuft cells and facilitate the unconventional IL-33 secretion via GSDMC membrane pores.
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影响因子：
7.8
作者：
Allen JE;Sutherland TE
通讯作者：
Sutherland TE
影响因子：
64.8
作者：
Gerbe F;Sidot E;Smyth DJ;Ohmoto M;Matsumoto I;Dardalhon V;Cesses P;Garnier L;Pouzolles M;Brulin B;Bruschi M;Harcus Y;Zimmermann VS;Taylor N;Maizels RM;Jay P
通讯作者：
Jay P
簇细胞，味觉化学细胞，在肠道中编排寄生虫2型免疫力。
DOI：
10.1126/science.aaf1648
发表时间：
2016-03-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Howitt MR;Lavoie S;Michaud M;Blum AM;Tran SV;Weinstock JV;Gallini CA;Redding K;Margolskee RF;Osborne LC;Artis D;Garrett WS
通讯作者：
Garrett WS
影响因子：
7.7
作者：
Ferrer-Font, Laura;Mehta, Palak;Mayer, Johannes U.
通讯作者：
Mayer, Johannes U.
影响因子：
7
作者：
Billipp TE;Nadjsombati MS;von Moltke J
通讯作者：
von Moltke J