Mutations in the death receptor FAS 1 , 2 or its ligand FASL 3 cause autoimmune lymphoproliferative syndrome, whereas mutations in caspase-8 or its adaptor FADD—which mediate cell death downstream of FAS and FASL—cause severe immunodeficiency in addition to autoimmune lymphoproliferative syndrome 4 – 6 . Mouse models have corroborated a role for FADD–caspase-8 in promoting inflammatory responses 7 – 12 , but the mechanisms that underlie 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 the production of select cytokines upon stimulation of the Toll-like receptor (TLR)1–TLR2 heterodimer (referred to herein as TLR1/2), TLR7 or TLR9, but not upon engagement of TLR3 or TLR4. N4BP1 did not suppress TLR3 or TLR4 responses in wild-type macrophages, owing to TRIF- and caspase-8-dependent cleavage of N4BP1. Notably, the impaired production of cytokines in response to TLR3 and TLR4 stimulation of caspase-8-deficient macrophages 13 was largely rescued by co-deletion of N4BP1. Thus, the persistence of intact N4BP1 in caspase-8-deficient macrophages impairs their ability to mount robust cytokine responses. Tumour 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 mutations of FADD and caspase-8. NEDD4-binding protein 1 (N4BP1) is identified as a suppressor of cytokine production that is inactivated by caspase-8, which provides insight into the mechanisms underlying the immunodeficiency caused by mutations in FADD and caspase-8.

中文翻译：

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通过 Caspase-8 切割 N4BP1 整合先天免疫信号

死亡受体 FAS 1、2 或其配体 FASL 3 的突变会导致自身免疫性淋巴组织增生综合征，而 caspase-8 或其接头 FADD（介导 FAS 和 FASL 下游的细胞死亡）的突变会导致严重的免疫缺陷以及自身免疫性淋巴组织增生综合征 4 – 6 。小鼠模型已证实 FADD-caspase-8 在促进炎症反应中的作用 7 – 12 ，但免疫缺陷的潜在机制仍未确定。在这里，我们将 NEDD4 结合蛋白 1 (N4BP1) 鉴定为被 caspase-8 切割和灭活的细胞因子产生的抑制剂。小鼠中 N4BP1 缺失在刺激 Toll 样受体 (TLR)1-TLR2 异二聚体（本文称为 TLR1/2）、TLR7 或 TLR9 时增加了选择细胞因子的产生，但在 TLR3 或 TLR4 参与时不增加。由于 N4BP1 的 TRIF 和 caspase-8 依赖性切割，N4BP1 不抑制野生型巨噬细胞中的 TLR3 或 TLR4 反应。值得注意的是，响应于 TLR3 和 TLR4 刺激 caspase-8 缺陷型巨噬细胞 13 的细胞因子产生受损在很大程度上通过 N4BP1 的共缺失得以挽救。因此，在缺乏 caspase-8 的巨噬细胞中持续存在完整的 N4BP1 会削弱它们产生强烈细胞因子反应的能力。像 TLR3 或 TLR4 激动剂一样，肿瘤坏死因子 (TNF) 也诱导 N4BP1 的 caspase-8 依赖性切割，从而使不依赖 TRIF 的 TLR 产生更高水平的炎性细胞因子。总的来说，我们的结果将 N4BP1 确定为细胞因子反应的有效抑制因子。揭示 caspase-8 对 N4BP1 的切割作为炎症过程中的信号整合点；并解释由 FADD 和 caspase-8 突变引起的免疫缺陷。NEDD4 结合蛋白 1 (N4BP1) 被鉴定为被 caspase-8 灭活的细胞因子产生的抑制因子，这提供了对由 FADD 和 caspase-8 突变引起的免疫缺陷的潜在机制的深入了解。