美国基因泰克公司Vishva M. Dixit、Kim Newton和斯坦福大学医学院Alexander D. Gitlin研究组合作取得新进展。他们发现Caspase-8通过切割N4BP1整合先天免疫信号。该研究在线发表在2020年9月24日出版的《自然》杂志上。
研究人员发现NEDD4结合蛋白1（N4BP1）被caspase-8切割并失活，N4BP1是细胞因子产生的抑制剂。缺失N4BP1的小鼠在Toll样受体（TLR）1/2、TLR7或TLR9的刺激下增加了选择性细胞因子的产生，但该过程不会发生在TLR3或TLR4诱导的反应中。N4BP1不会抑制野生型巨噬细胞中TLR3或TLR4的反应，这是由TRIF和caspase-8依赖性切割N4BP1所致。
值得注意的是，在caspase-8缺失的巨噬细胞中TLR3和TLR4细胞因子应答受损可通过共缺失N4BP1挽救。因此，完整N4BP1在caspase-8缺陷巨噬细胞中的持久存在会减弱其建立稳定细胞因子反应的能力。肿瘤坏死因子（TNF），如TLR3或TLR4的激动剂，也会引起caspase-8依赖性切割N4BP1，从而导致TRIF依赖性TLR产生更多的炎性细胞因子。
总的来说，该研究结果表明N4BP1是细胞因子应答的有效抑制剂，并揭示了Caspase8对N4BP1的切割是炎症信号的整合点；并解释由FADD-caspase-8突变引起的免疫缺陷。
据悉，死亡受体Fas或其配体FasL的突变会引起自身免疫性淋巴组织增生综合征（ALPS），而突变Fas/FasL介导的细胞死亡下游因子caspase-8或其配体FADD除了导致ALPS外还会产生严重的免疫缺陷。小鼠模型也证实了FADD-caspase-8在促进炎症反应中的功能，但免疫缺陷的潜在机制仍然未知。
附：英文原文
Title:Integration of innate immune signaling by caspase-8 cleavage of N4BP1
Author:Alexander D. Gitlin, Klaus Heger, Alexander F. Schubert, Rohit Reja, Donghong Yan, Victoria C. Pham, Eric Suto, Juan Zhang, Youngsu C. Kwon, Emily C. Freund, Jing Kang, Anna Pham, Roger Caothien, Natasha Bacarro, Trent Hinkle, Min Xu, Brent S. McKenzie, Benjamin Haley, Wyne P. Lee, Jennie R. Lill, Merone Roose-Girma, Monika Dohse, Joshua D. Webster, Kim Newton & Vishva M. Dixit
Issue&Volume:24 September 2020
Abstract: Mutations in the death receptor Fas1,2 or its ligand FasL3 cause autoimmune lymphoproliferative syndrome (ALPS), whereas mutations in caspase-8 or its adaptor FADD – which mediate cell death downstream of Fas/FasL – cause severe immunodeficiency in addition to ALPS4–6. Mouse models have corroborated a role for FADD-caspase-8 in promoting inflammatory responses7–12, but the mechanisms underlying immunodeficiency remain undefined. Here, we identify NEDD4-binding protein 1 (N4BP1) as a suppressor of cytokine production that is cleaved and inactivated by caspase-8. N4BP1 deletion in mice increased production of select cytokines upon Toll-like receptor (TLR) 1/2, TLR7, or TLR9 stimulation, but not upon TLR3 or TLR4 engagement. N4BP1 did not suppress TLR3 or TLR4 responses in wild-type macrophages owing to TRIF- and caspase-8-dependent cleavage of N4BP1. Notably, impaired TLR3 and TLR4 cytokine responses of caspase-8-deficient macrophages13 were largely rescued by co-deletion of N4BP1. Thus, persistence of intact N4BP1 in caspase-8-deficient macrophages impairs their ability to mount robust cytokine responses. Tumor necrosis factor (TNF), like TLR3 or TLR4 agonists, also induced caspase-8-dependent cleavage of N4BP1, thereby licensing TRIF-independent TLRs to produce higher levels of inflammatory cytokines. Collectively, our results identify N4BP1 as a potent suppressor of cytokine responses; reveal N4BP1 cleavage by caspase-8 as a point of signal integration during inflammation; and offer an explanation for immunodeficiency caused by FADD-caspase-8 mutations.
DOI:https://doi.org/10.1038/s41586-020-2796-5
Source: https://www.nature.com/articles/s41586-020-2796-5
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
