FUT2-dependent fucosylation of HYOU1 protects intestinal stem cells against inflammatory injury by regulating unfolded protein response.
FUT2-dependent fucosylation of HYOU1 protects intestinal stem cells against inflammatory injury by regulating unfolded protein response.
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fut2依赖的HYOU1聚焦通过调节未折叠蛋白反应保护肠道干细胞免受炎症损伤。
DOI：
10.1016/j.redox.2023.102618
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发表时间：
2023-04
期刊：
影响因子：
11.4
通讯作者：
Hou, Xiaohua
中科院分区：
文献类型：
--
作者：
Wang, Zhe;Tan, Chen;Duan, Caihan;Wu, Junhao;Zhou, Dan;Hou, Lingzhi;Qian, Wei;Han, Chaoqun;Hou, Xiaohua
肠上皮损伤后的修复是由肠干细胞（ISCs）协调的。肠上皮聚焦转移酶2 （FUT2）催化的聚焦化有利于粘膜愈合，但对ISCs的影响尚不明确。采用葡聚糖硫酸钠（DSS）和脂多糖（LPS）模型评价FUT2对损伤后ISCs的作用。采用LPS和聚焦培养的WT和Fut2ΔISC （isc特异性Fut2敲除）小鼠肠道类器官，分析isc的凋亡、功能和干性。利用n -糖蛋白组学、UEA-1层析和位点定向诱变等方法分析调控机制，鉴定靶蛋白和相应的修饰位点。聚焦可通过上调ISCs的FUT2和α-1,2-聚焦化来减轻肠上皮损伤。氧化应激、线粒体功能障碍和细胞凋亡均受到病灶的抑制。与此同时，LPS处理的肠道类器官的生长和增殖能力得到了维持。相反，在ISCs中，FUT2的缺失通过lps诱导的内质网（ER）应激升高，启动未折叠蛋白反应（UPR）的IRE1/TRAF2/ASK1/JNK分支，加重了ISCs的上皮损伤，破坏了ISCs的生长和增殖能力。发现FUT2介导的天冬酰胺（Asn） 862 n -糖基化位点的伴侣蛋白HYOU1的集中化促进了ISCs的生存和自我更新，并提高了ISCs对内质网应激和炎症损伤的抵抗。我们的研究强调了ISCs抗炎症的聚焦依赖性保护机制，这可能为治疗肠道损伤疾病提供了一种迷人的策略。肠干细胞聚焦化驱动损伤后上皮修复。FUT2抑制肠道类器官的氧化应激、细胞凋亡和干性丧失。肠道干细胞FUT2缺失加剧内质网应激。聚焦的HYOU1增强干细胞对促凋亡IRE1信号的抗性。
The intestinal epithelial repair after injury is coordinated by intestinal stem cells (ISCs). Fucosylation catalyzed by fucosyltransferase 2 (FUT2) of the intestinal epithelium is beneficial to mucosal healing but poorly defined is the influence on ISCs. The dextran sulfate sodium (DSS) and lipopolysaccharide (LPS) model were used to assess the role of FUT2 on ISCs after injury. The apoptosis, function, and stemness of ISCs were analyzed using intestinal organoids from WT and Fut2ΔISC (ISC-specific Fut2 knockout) mice incubated with LPS and fucose. N-glycoproteomics, UEA-1 chromatography, and site-directed mutagenesis were monitored to dissect the regulatory mechanism, identify the target fucosylated protein and the corresponding modification site. Fucose could alleviate intestinal epithelial damage via upregulating FUT2 and α-1,2-fucosylation of ISCs. Oxidative stress, mitochondrial dysfunction, and cell apoptosis were impeded by fucose. Meanwhile, fucose sustained the growth and proliferation capacity of intestinal organoids treated with LPS. Contrarily, FUT2 depletion in ISCs aggravated the epithelial damage and disrupted the growth and proliferation capacity of ISCs via escalating LPS-induced endoplasmic reticulum (ER) stress and initiating the IRE1/TRAF2/ASK1/JNK branch of unfolded protein response (UPR). Fucosylation of the chaperone protein HYOU1 at the N-glycosylation site of asparagine (Asn) 862 mediated by FUT2 was identified to facilitate ISCs survival and self-renewal, and improve ISCs resistance to ER stress and inflammatory injury. Our study highlights a fucosylation-dependent protective mechanism of ISCs against inflammation, which may provide a fascinating strategy for treating intestinal injury disorders. Fucosylation of intestinal stem cells drives epithelial repair after injury. FUT2 restains oxidative stress, apoptosis, and stemness loss in intestinal organoids. FUT2 depletion in intestinal stem cells exacerbates endoplasmic reticulum stress. Fucosylated HYOU1 enhances stem cell resistance to pro-apoptotic IRE1 signaling.
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影响因子：
--
作者：
Ma D;Jiang P;Jiang Y;Li H;Zhang D
通讯作者：
Zhang D
影响因子：
4.8
作者：
Li, Ying;Jiang, Yudong;Lin, Rong
通讯作者：
Lin, Rong
影响因子：
64.5
作者：
Hotamisligil GS
通讯作者：
Hotamisligil GS
影响因子：
64.8
作者：
Drost, Jarno;van Jaarsveld, Richard H.;Clevers, Hans
通讯作者：
Clevers, Hans
DOI：
10.1016/j.trsl.2021.06.001
发表时间：
2021-10
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
Liu CY;Cham CM;Chang EB
通讯作者：
Chang EB