Department of Microbiology & Immunology, School of Medicine, New York Medical College, Valhalla, NY, 10595, USA.
Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, 06030, USA.
Commun Biol. 2020 Oct 8;3(1):556. doi: 10.1038/s42003-020-01285-6.
Macrophage scavenger receptor 1 (MSR1) mediates the endocytosis of modified low-density lipoproteins and plays an important antiviral role. However, the molecular mechanism underlying MSR1 antiviral actions remains elusive. We report that MSR1 activates autophagy to restrict infection of Chikungunya virus (CHIKV), an arthritogenic alphavirus that causes acute and chronic crippling arthralgia. Msr1 expression was rapidly upregulated after CHIKV infection in mice. Msr1 knockout mice had elevated viral loads and increased susceptibility to CHIKV arthritis along with a normal type I IFN response. Induction of LC3 lipidation by CHIKV, a marker of autophagy, was reduced in Msr1 cells. Mechanistically, MSR1 interacted with ATG12 through its cytoplasmic tail and this interaction was enhanced by CHIKV nsP1 protein. MSR1 repressed CHIKV replication through ATG5-ATG12-ATG16L1 and this was dependent on the FIP200-and-WIPI2-binding domain, but not the WD40 domain of ATG16L1. Our results elucidate an antiviral role for MSR1 involving the autophagic function of ATG5-ATG12-ATG16L1.
巨噬细胞清道夫受体 1（MSR1）介导修饰的低密度脂蛋白的内吞作用，并发挥重要的抗病毒作用。然而，MSR1 抗病毒作用的分子机制仍不清楚。我们报告 MSR1 通过自噬来限制基孔肯雅病毒（CHIKV）的感染，CHIKV 是一种引起急性和慢性致残性关节炎的致关节炎阿尔法病毒。在小鼠感染 CHIKV 后，MSR1 的表达迅速上调。Msr1 基因敲除小鼠的病毒载量升高，对 CHIKV 关节炎的易感性增加，同时伴有正常的 I 型 IFN 反应。CHIKV 诱导的 LC3 脂质化，这是自噬的标志物，在 Msr1 细胞中减少。从机制上讲，MSR1 通过其细胞质尾巴与 ATG12 相互作用，而 CHIKV nsP1 蛋白增强了这种相互作用。MSR1 通过 ATG5-ATG12-ATG16L1 抑制 CHIKV 复制，这依赖于 FIP200 和 WIPI2 结合域，但不依赖于 ATG16L1 的 WD40 结构域。我们的研究结果阐明了 MSR1 的抗病毒作用，涉及 ATG5-ATG12-ATG16L1 的自噬功能。
