The WD and linker domains of ATG16L1 required for non-canonical autophagy limit lethal respiratory infection by influenza A virus at epithelial surfaces
The WD and linker domains of ATG16L1 required for non-canonical autophagy limit lethal respiratory infection by influenza A virus at epithelial surfaces
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非典型自噬所需的 ATG16L1 的 WD 和连接结构域限制了上皮表面甲型流感病毒的致命呼吸道感染
DOI：
10.1101/2020.01.15.907873
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Wang Y
吞噬作用和自噬代表了两种进化上古老的途径，它们通过将病原体递送到溶酶体进行降解来提供对感染的重要防御。吞噬作用和自噬通过非经典的自噬途径连接，所述非经典的自噬途径将LC 3缀合至内-溶酶体区室以促进吞噬体成熟和溶酶体融合。体外细胞研究暗示了非典型自噬在宿主防御中的作用，但至关重要的是，这些研究很少扩展到具有完整上皮屏障和复杂免疫系统的模型生物体的感染。为了解决这个问题，我们通过去除将LC 3募集到内-溶酶体区室所需的WD和ATG 16 L1的接头结构域，开发了具有非典型自噬特异性丧失的小鼠模型。小鼠保留了常规自噬所需的ATG 16 L1的卷曲螺旋结构域，并维持组织和免疫稳态。具有非典型自噬的全身性丧失的小鼠对低致病性鼠适应的甲型流感病毒非常敏感，导致整个肺部的广泛病毒复制、细胞因子失调、暴发性肺炎和肺部炎症，导致与强毒株相关的高死亡率。有条件的小鼠模型和离体分析表明，对IAV感染肺的保护需要上皮屏障内的非典型自噬，但不依赖于吞噬细胞和其他白细胞。这在上皮细胞中建立了非经典的自噬途径，作为一种新的先天防御机制，可以限制粘膜表面的IAV感染。
Phagocytosis and autophagy represent two evolutionarily ancient pathways that provide an important defense against infection by delivering pathogens to lysosomes for degradation. Phagocytosis and autophagy are linked by non-canonical autophagy pathways that conjugate LC3 to endo-lysosome compartments to facilitate phagosome maturation and lysosome fusion. A role for non-canonical autophagy in host defence is implied from cellular studies in vitro, but critically, these studies have rarely been extended to infection of model organisms with intact epithelial barriers and complex immune systems. To address this, we developed a mouse model with specific loss of non-canonical autophagy by removing the WD and linker domain of ATG16L1 required for recruitment of LC3 to endo-lysosome compartments. The mice retain the coiled-coiled domain of ATG16L1 required for conventional autophagy and maintain tissue and immunological homeostasis. Mice with systemic loss of non-canonical autophagy are exquisitely sensitive to low-pathogenicity murine-adapted influenza A virus leading to extensive viral replication throughout the lungs, cytokine dysregulation, fulminant pneumonia and lung inflammation leading to high mortality associated with virulent strains. Conditional mouse models and ex vivo analysis showed that protection against IAV infection of lung required non-canonical autophagy within epithelial barriers but was independent of phagocytes and other leukocytes. This establishes non-canonical autophagy pathways in epithelial cells as a novel innate defence mechanism that can restrict IAV infection at mucosal surfaces.
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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
LC3相关的吞噬作用限制细胞内细菌病原体杜莫菲军团菌
DOI：
--
发表时间：
2016
期刊：
影响因子：
--
作者：
Andree Hubber;久堀智子、Cevayir Coban;松澤健志、永井宏樹
通讯作者：
松澤健志、永井宏樹
影响因子：
5.6
作者：
Heckmann BL;Boada-Romero E;Cunha LD;Magne J;Green DR
通讯作者：
Green DR
影响因子：
6.7
作者：
Matte C;Casgrain PA;Séguin O;Moradin N;Hong WJ;Descoteaux A
通讯作者：
Descoteaux A
影响因子：
30.3
作者：
Gluschko, Alexander;Herb, Marc;Schramm, Michael
通讯作者：
Schramm, Michael