State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, China.
College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China.
Autophagy. 2021 Nov;17(11):3763-3775. doi: 10.1080/15548627.2021.1897223. Epub 2021 Mar 14.
Macroautophagy/autophagy plays a critical role in antiviral immunity through targeting viruses and initiating host immune responses. The receptor protein, SQSTM1/p62 (sequestosome 1), plays a vital role in selective autophagy. It serves as a receptor targeting ubiquitinated proteins or pathogens to phagophores for degradation. In this study, we explored the reciprocal regulation between selective autophagy receptor SQSTM1 and Seneca Valley virus (SVV). SVV infection induced autophagy. Autophagy promoted SVV infection in pig cells but played opposite functions in human cells. Overexpression of SQSTM1 decreased viral protein production and reduced viral titers. Further study showed that SQSTM1 interacted with SVV VP1 and VP3 independent of its UBA domain. SQSTM1 targeted SVV VP1 and VP3 to phagophores for degradation to inhibit viral replication. To counteract this, SVV evolved strategies to circumvent the host autophagic machinery to promote viral replication. SVV 3C targeted the receptor SQSTM1 for cleavage at glutamic acid 355, glutamine 392, and glutamine 395 and abolished its capacity to mediate selective autophagy. At the same time, the 3C-mediated SQSTM1 cleavage products lost the ability to inhibit viral propagation. Collectively, our results provide evidence for selective autophagy in host against viruses and reveal potential viral strategies to evade autophagic machinery for successful pathogenesis. Baf.A1: bafilomycin A; Co-IP: co-immunoprecipitation; hpi: h post-infection; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MOI: multiplicity of infection; PB1: N-terminal Phox/Bem1p; Rap.: rapamycin; Seneca Valley virus: SVV; SQSTM1/p62: sequestosome 1; SQSTM1-N355: residues 1 to 355 of SQSTM1; SQSTM1-C355: residues 355 to 478 of SQSTM1; SQSTM1-N392: residues 1 to 392 of SQSTM1; SQSTM1-C392: residues 392 to 478 of SQSTM1; SQSTM1-N388: residues 1 to 388 of SQSTM1; SQSTM1-N397: residues 1 to 397 of SQSTM1; UBA: ubiquitin association; Ubi: ubiquitin.
自噬在抗病毒免疫中通过靶向病毒和启动宿主免疫反应起着关键作用。受体蛋白 SQSTM1/p62（自噬体相关蛋白 1）在选择性自噬中起着至关重要的作用。它作为一种受体，可将泛素化蛋白或病原体靶向到吞噬体进行降解。在这项研究中，我们探讨了选择性自噬受体 SQSTM1 与森那利瓦病毒（SVV）之间的相互调节关系。SVV 感染诱导自噬。自噬促进猪细胞中的 SVV 感染，但在人细胞中则起到相反的作用。过表达 SQSTM1 可降低病毒蛋白的产生并降低病毒滴度。进一步的研究表明，SQSTM1 与 SVV VP1 和 VP3 相互作用，不依赖其 UBA 结构域。SQSTM1 将 SVV VP1 和 VP3 靶向到吞噬体进行降解，从而抑制病毒复制。为了对抗这种情况，SVV 进化出了策略来规避宿主自噬机制，以促进病毒复制。SVV 3C 靶向受体 SQSTM1，在谷氨酸 355、谷氨酰胺 392 和谷氨酰胺 395 处进行切割，并使其丧失介导选择性自噬的能力。同时，3C 介导的 SQSTM1 切割产物丧失了抑制病毒增殖的能力。总的来说，我们的研究结果为宿主针对病毒的选择性自噬提供了证据，并揭示了病毒逃避自噬机制以成功发病的潜在策略。Baf.A1：巴弗洛霉素 A；Co-IP：免疫共沉淀；hpi：感染后 h；LIR：LC3 相互作用区域；MAP1LC3B/LC3B：微管相关蛋白 1 轻链 3β；MOI：感染复数；PB1：N 端 Phox/Bem1p；Rap.：雷帕霉素；森那利瓦病毒：SVV；SQSTM1/p62：自噬体相关蛋白 1；SQSTM1-N355：SQSTM1 的 1 至 355 个残基；SQSTM1-C355：SQSTM1 的 355 至 478 个残基；SQSTM1-N392：SQSTM1 的 1 至 392 个残基；SQSTM1-C392：SQSTM1 的 392 至 478 个残基；SQSTM1-N388：SQSTM1 的 1 至 388 个残基；SQSTM1-N397：SQSTM1 的 1 至 397 个残基；UBA：泛素结合；Ubi：泛素。
