Non-canonical autophagy functions of ATG16L1 in epithelial cells limit lethal infection by influenza A virus.
Non-canonical autophagy functions of ATG16L1 in epithelial cells limit lethal infection by influenza A virus.
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DOI：
10.15252/embj.2020105543
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发表时间：
2021-03-15
期刊：
影响因子：
--
通讯作者：
Wileman T
中科院分区：
文献类型：
--
作者：
Wang Y;Sharma P;Jefferson M;Zhang W;Bone B;Kipar A;Bitto D;Coombes JL;Pearson T;Man A;Zhekova A;Bao Y;Tripp RA;Carding SR;Yamauchi Y;Mayer U;Powell PP;Stewart JP;Wileman T
甲型流感病毒（IAV）和SARS - CoV - 2 （COVID - 19）引起大流行感染，其中细胞因子风暴综合征和肺部炎症导致高死亡率。鉴于呼吸道病毒的高社会和经济成本，迫切需要了解呼吸道如何抵御病毒感染。在这里，我们使用缺乏ATG16L1的WD和连接域的小鼠来证明ATG16L1依赖的LC3靶向单膜非自噬体室（称为非典型自噬）可以保护小鼠免受致命的IAV感染。全身非典型自噬丧失的小鼠对低致病性IAV非常敏感，在这种情况下，病毒在整个肺部广泛复制，加上由浆细胞样树突状细胞介导的细胞因子扩增，导致暴发性肺炎、肺部炎症和高死亡率。IAV被控制在上皮屏障内，其中非典型自噬减少了IAV与核内体的融合和干扰素信号的激活。条件小鼠模型和离体分析表明，肺对IAV感染的保护作用不依赖于吞噬细胞和其他白细胞。这表明气道上皮细胞中的非典型自噬是一种新的先天防御，可以限制IAV感染和呼吸道表面的致死性炎症。缺失介导ATG16L1非规范功能的WD结构域使小鼠对流感感染后的细胞因子风暴和致死性肺炎敏感。
Influenza A virus (IAV) and SARS‐CoV‐2 (COVID‐19) cause pandemic infections where cytokine storm syndrome and lung inflammation lead to high mortality. Given the high social and economic cost of respiratory viruses, there is an urgent need to understand how the airways defend against virus infection. Here we use mice lacking the WD and linker domains of ATG16L1 to demonstrate that ATG16L1‐dependent targeting of LC3 to single‐membrane, non‐autophagosome compartments – referred to as non‐canonical autophagy – protects mice from lethal IAV infection. Mice with systemic loss of non‐canonical autophagy are exquisitely sensitive to low‐pathogenicity IAV where extensive viral replication throughout the lungs, coupled with cytokine amplification mediated by plasmacytoid dendritic cells, leads to fulminant pneumonia, lung inflammation and high mortality. IAV was controlled within epithelial barriers where non‐canonical autophagy reduced IAV fusion with endosomes and activation of interferon signalling. Conditional mouse models and ex vivo analysis showed that protection against IAV infection of lung was independent of phagocytes and other leucocytes. This establishes non‐canonical autophagy in airway epithelial cells as a novel innate defence that restricts IAV infection and lethal inflammation at respiratory surfaces. Deletion of WD domain mediating non‐canonical functions of ATG16L1 sensitizes mice to cytokine storm and lethal pneumonia upon influenza infection.
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DOI：
10.1038/nri3665
发表时间：
2014-05
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
30.3
作者：
Lu Q;Yokoyama CC;Williams JW;Baldridge MT;Jin X;DesRochers B;Bricker T;Wilen CB;Bagaitkar J;Loginicheva E;Sergushichev A;Kreamalmeyer D;Keller BC;Zhao Y;Kambal A;Green DR;Martinez J;Dinauer MC;Holtzman MJ;Crouch EC;Beatty W;Boon AC;Zhang H;Randolph GJ;Artyomov MN;Virgin HW
通讯作者：
Virgin HW
非规范自噬抑制自身炎症，类似狼疮的对垂死细胞的反应。
影响因子：
64.8
作者：
Martinez J;Cunha LD;Park S;Yang M;Lu Q;Orchard R;Li QZ;Yan M;Janke L;Guy C;Linkermann A;Virgin HW;Green DR
通讯作者：
Green DR
影响因子：
7.3
作者：
Lamprinaki D;Beasy G;Zhekova A;Wittmann A;James S;Dicks J;Iwakura Y;Saijo S;Wang X;Chow CW;Roberts I;Korcsmaros T;Mayer U;Wileman T;Kawasaki N
通讯作者：
Kawasaki N
影响因子：
4.6
作者：
Hubber A;Kubori T;Coban C;Matsuzawa T;Ogawa M;Kawabata T;Yoshimori T;Nagai H
通讯作者：
Nagai H