Multiple truncated isoforms of MAVS prevent its spontaneous aggregation in antiviral innate immune signalling.
Multiple truncated isoforms of MAVS prevent its spontaneous aggregation in antiviral innate immune signalling.
复制标题
MAVS 的多个截短亚型可防止其在抗病毒先天免疫信号中自发聚集。
DOI：
10.1038/ncomms15676
复制
发表时间：
2017-06-13
影响因子：
16.6
通讯作者：
Hou F
中科院分区：
文献类型：
--
作者：
Qi N;Shi Y;Zhang R;Zhu W;Yuan B;Li X;Wang C;Zhang X;Hou F
作为对病毒感染的响应，RIG-I样受体(RLRs)感知病毒RNA，并诱导MAV形成类病毒蛋白聚集体，进一步传播抗病毒信号。虽然单体MAVS重组蛋白在体外可以自发地组装成类病毒的细丝，但内源性MAVS在细胞内的聚集在病毒感染之前是不能被阻止的。阻止细胞MAV自发聚集的机制尚不清楚。在这里，我们证明了多个N端截短的MAV亚型在阻止全长MAV通过跨膜区介导的同型相互作用自发聚集方面是必不可少的。如果没有这些较短的异构体，全长MAV容易自发聚集和NIX介导的丝裂原降解。在没有N末端截短形式的情况下，阻断Nix介导的有丝分裂吞噬稳定全长MAV，其自发聚集并诱导随后的I型干扰素和其他促炎细胞因子的表达。因此，我们的数据揭示了防止内源性MAV自发聚集以避免意外激活抗病毒天然免疫信号的重要机制。MAVS是病原体感知机制的重要组成部分，其功能是形成类似于普里恩的细丝。在这里，作者展示了截短的内源性MAVs的替代翻译形式可以防止细胞中的自发聚集和降解，以维持MAVS介导的免疫信号。
In response to virus infection, RIG-I-like receptors (RLRs) sense virus RNA and induce MAVS to form prion-like aggregates to further propagate antiviral signalling. Although monomeric MAVS recombinant protein can assemble into prion-like filaments spontaneously in vitro, endogenous MAVS in cells is prevented from aggregation until viral infection. The mechanism preventing cellular MAVS from spontaneous aggregation is unclear. Here we show that multiple N-terminal truncated isoforms of MAVS are essential in preventing full-length MAVS from spontaneous aggregation through transmembrane domain-mediated homotypic interaction. Without these shorter isoforms, full-length MAVS is prone to spontaneous aggregation and Nix-mediated mitophagic degradation. In the absence of N-terminally truncated forms, blocking Nix-mediated mitophagy stabilizes full-length MAVS, which aggregates spontaneously and induces the subsequent expression of type I interferon and other proinflammatory cytokines. Our data thus uncover an important mechanism preventing spontaneous aggregation of endogenous MAVS to avoid accidental activation of antiviral innate immune signalling. MAVS is an essential component of the pathogen-sensing machinery, and functions by forming prion-like filaments. Here the authors show that alternatively translated forms of truncated endogenous MAVS can prevent spontaneous aggregation and degradation in cells to sustain MAVS-mediated immune signalling.