Inherited deficiency of zinc finger NFX1-type containing 1 (ZNFX1), a dsRNA virus sensor, is associated with severe familial immunodeficiency, multisystem inflammatory disease, increased susceptibility to viruses, and early mortality. However, limited treatments for patients with pathological variants of ZNFX1 exist due to an incomplete understanding of the diseases resulting from ZNFX1 mutations. Here, we demonstrate that ZNFX1 specifically inhibits the activation of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome in response to NLRP3 activators both in vitro and in vivo. ZNFX1 retains NLRP3 in the cytoplasm and prevents its accumulation in the TGN38 + /TGN46+ vesicles in the resting state. Upon NLRP3 inflammasome activation, ZNFX1 is cleaved by caspase-1, establishing a feed-forward loop that promotes NLRP3 accumulation in the trans-Golgi network (TGN) and amplifies the activity of the downstream cascade. Expression of wild-type ZNFX1, but not of ZNFX1 with human pathogenic mutations, rescues the impairment of NLRP3 inflammasome inhibition. Our findings reveal a dual role of ZNFX1 in virus sensing and suppression of inflammation, which may become valuable for the development of treatments for ZNFX1 mutation-related diseases.

中文翻译：

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人类疾病相关基因 ZNFX1 通过抑制 NLRP3 炎性小体来控制炎症。


包含 1 的锌指 NFX1 型遗传性缺陷症 （ZNFX1） 是一种 dsRNA 病毒传感器，与严重的家族性免疫缺陷、多系统炎症性疾病、病毒易感性增加和早期死亡有关。然而，由于对 ZNFX1 突变引起的疾病的了解不完整，对具有 ZNFX1 病理变异的患者的治疗有限。在这里，我们证明 ZNFX1 在体外和体内响应 NLRP3 激活剂特异性抑制 NLR 家族含 pyrin 结构域蛋白结构域蛋白 3 （NLRP3） 炎性小体的激活。ZNFX1 将 NLRP3 保留在细胞质中，并防止其在静息状态下在 TGN38 + /TGN46 + 囊泡中积累。NLRP3 炎性小体激活后，ZNFX1 被 caspase-1 裂解，建立一个前馈环，促进 NLRP3 在反式高尔基体网络 （TGN） 中的积累并放大下游级联反应的活性。野生型 ZNFX1 的表达，而不是具有人类致病性突变的 ZNFX1 的表达，挽救了 NLRP3 炎性小体抑制的损害。我们的研究结果揭示了 ZNFX1 在病毒感应和抑制炎症方面的双重作用，这可能对 ZNFX1 突变相关疾病的治疗开发具有价值。