GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis.
GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis.
复制标题
GSDMB在IBD中增加，并调节上皮恢复/修复，而不依赖于焦亡。
DOI：
10.1016/j.cell.2021.12.024
复制
发表时间：
2022-01-20
期刊：
影响因子：
64.5
通讯作者：
Pizarro TT
中科院分区：
文献类型：
--
作者：
Rana N;Privitera G;Kondolf HC;Bulek K;Lechuga S;De Salvo C;Corridoni D;Antanaviciute A;Maywald RL;Hurtado AM;Zhao J;Huang EH;Li X;Chan ER;Simmons A;Bamias G;Abbott DW;Heaney JD;Ivanov AI;Pizarro TT
Gasdermins是一个结构相关蛋白家族，最初被描述为在细胞凋亡中的作用。Gasdermin B（GSDMB）是目前研究最少的，虽然它与慢性粘膜炎性疾病的遗传易感性的关联是公认的，但其在活动性疾病状态期间的功能相关性知之甚少。在此，我们报告了炎症性肠病中GSDMB的增加，单细胞分析鉴定了上皮细胞对发炎的结肠细胞/隐窝顶结肠细胞的特异性。令人惊讶的是，机制实验和转录组分析揭示了在活化的上皮细胞和类器官中缺乏固有的GSDMB依赖性焦亡，而是指出在体外伤口闭合期间增殖和迁移增加，这在GSDMB缺陷细胞中停滞，所述GSDMB缺陷细胞显示依赖于PDGF-A介导的FAK磷酸化的基于黏着斑蛋白的肌动球蛋白应激纤维的过度增殖和增强的形成。重要的是，携带疾病相关的GSDMB SNP赋予破坏上皮恢复/修复的功能缺陷，这共同确立了GSDMB作为恢复上皮屏障功能和解决炎症的关键因素。gasdermin B调节粘着斑激酶磷酸化，以促进上皮细胞的维持和修复，这与其在热变性细胞死亡中的既定作用无关。与炎症性肠病相关的自然发生的突变破坏了这一作用。
Gasdermins are a family of structurally-related proteins originally described for their role in pyroptosis. Gasdermin B (GSDMB) is currently the least studied, and while its association with genetic susceptibility to chronic, mucosal inflammatory disorders is well-established, little is known of its functional relevance during active disease states. Herein, we report increased GSDMB in inflammatory bowel disease, with single-cell analysis identifying epithelial specificity to inflamed colonocytes/crypt top colonocytes. Surprisingly, mechanistic experiments and transcriptome profiling reveal lack of inherent GSDMB-dependent pyroptosis in activated epithelial cells and organoids, but instead, point to increased proliferation and migration during in vitro wound closure, which arrests in GSDMB-deficient cells that display hyper-adhesiveness and enhanced formation of vinculin-based actomyosin stress fibers dependent on PDGF-A-mediated FAK phosphorylation. Importantly, carriage of disease-associated GSDMB SNPs confers functional defects disrupting epithelial restitution/repair, which altogether, establishes GSDMB as a critical factor for restoration of epithelial barrier function and the resolution of inflammation. Independently from its established role in pyroptotic cell death, gasdermin B regulates focal adhesion kinase phosphorylation to promote epithelial maintenance and repair. Naturally occurring mutations associated with inflammatory bowel disease disrupt this role.
登录
查看更多内容
影响因子：
4.6
作者：
Hu YL;Lu S;Szeto KW;Sun J;Wang Y;Lasheras JC;Chien S
通讯作者：
Chien S
形成孔的蛋白质加油D可以调节白细胞介素-1的巨噬细胞分泌。
影响因子：
32.4
作者：
Evavold CL;Ruan J;Tan Y;Xia S;Wu H;Kagan JC
通讯作者：
Kagan JC
影响因子：
82.9
作者：
Graham, W. Vallen;He, Weiqi;Turner, Jerrold R.
通讯作者：
Turner, Jerrold R.
影响因子：
24.5
作者：
Detjen, KM;Farwig, K;Rosewicz, S
通讯作者：
Rosewicz, S
影响因子：
4.8
作者：
Bailey, Kelly M.;Liu, Jun
通讯作者：
Liu, Jun