Department of Medicine, University of California, San Francisco, San Francisco, CA.
Department of Medicine, University of California, San Francisco, San Francisco, CA
J Exp Med. 2018 Jul 2;215(7):1839-1852. doi: 10.1084/jem.20180198. Epub 2018 Jun 21.
A20 () and ABIN-1 () are candidate susceptibility genes for inflammatory bowel disease and other autoimmune or inflammatory diseases, but it is unclear how these proteins interact in vivo to prevent disease. Here we show that intestinal epithelial cell (IEC)-specific deletion of either A20 or ABIN-1 alone leads to negligible IEC loss, whereas simultaneous deletion of both A20 and ABIN-1 leads to rapid IEC death and mouse lethality. Deletion of both A20 and ABIN-1 from enteroids causes spontaneous cell death in the absence of microbes or hematopoietic cells. Studies with enteroids reveal that A20 and ABIN-1 synergistically restrict death by inhibiting TNF-induced caspase 8 activation and RIPK1 kinase activity. Inhibition of RIPK1 kinase activity alone, or caspase inhibition combined with RIPK3 deletion, abrogates IEC death by blocking both apoptosis and necroptosis in A20 and ABIN-1 double-deficient cells. These data show that the disease susceptibility proteins A20 and ABIN-1 synergistically prevent intestinal inflammation by restricting IEC death and preserving tissue integrity.
A20()和 ABIN-1()是炎症性肠病和其他自身免疫或炎症性疾病的候选易感基因，但这些蛋白质如何在体内相互作用以预防疾病尚不清楚。在这里，我们表明，单独敲除肠上皮细胞（IEC）中的 A20 或 ABIN-1 不会导致 IEC 明显丢失，而同时敲除 A20 和 ABIN-1 则会导致 IEC 快速死亡和小鼠死亡。从类器官中敲除 A20 和 ABIN-1 会导致在没有微生物或造血细胞的情况下自发的细胞死亡。类器官研究表明，A20 和 ABIN-1 通过抑制 TNF 诱导的半胱天冬酶 8 激活和 RIPK1 激酶活性来协同抑制细胞死亡。单独抑制 RIPK1 激酶活性，或结合 caspase 抑制和 RIPK3 缺失，通过阻断 A20 和 ABIN-1 双缺失细胞中的凋亡和坏死来消除 IEC 死亡。这些数据表明，疾病易感性蛋白 A20 和 ABIN-1 通过限制 IEC 死亡和维持组织完整性来协同预防肠道炎症。
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