State Key Laboratory of Veterinary Etiological Biology and National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
College of Animal Science, Yangtze University, Jingzhou, China.
Front Cell Infect Microbiol. 2021 Aug 31;11:707107. doi: 10.3389/fcimb.2021.707107. eCollection 2021.
Endoplasmic reticulum (ER) stress-induced autophagy is closely associated with viral infection and propagation. However, the intrinsic link between ER stress, autophagy, and viral replication during foot-and-mouth disease virus (FMDV) infection is not fully elucidated. Our previous studies demonstrated that FMDV infection activated the ER stress-associated UPR of the PERK-eIF2a and ATF6 signaling pathway, whereas the IRE1a signaling was suppressed. We found that the activated-ATF6 pathway participated in FMDV-induced autophagy and FMDV replication, while the IRE1α pathway only affected FMDV replication. Further studies indicated that Sec62 was greatly reduced in the later stages of FMDV infection and blocked the activation of the autophagy-related IRE1α-JNK pathway. Moreover, it was also found that Sec62 promoted IRE1a phosphorylation and negatively regulated FMDV proliferation. Importantly, Sec62 may interact with LC3 to regulate ER stress and autophagy balance and eventually contribute to FMDV clearance fusing with lysosomes. Altogether, these results suggest that Sec62 is a critical molecule in maintaining and recovering ER homeostasis by activating the IRE1α-JNK pathway and delivering autophagosome into the lysosome, thus providing new insights on FMDV-host interactions and novel antiviral therapies.
内质网（ER）应激诱导的自噬与病毒感染和复制密切相关。然而，在口蹄疫病毒（FMDV）感染过程中，内质网应激、自噬和病毒复制之间的内在联系尚未完全阐明。我们之前的研究表明，FMDV 感染激活了 PERK-eIF2a 和 ATF6 信号通路相关的 ER 应激 UPR，而 IRE1a 信号被抑制。我们发现，激活的 ATF6 通路参与了 FMDV 诱导的自噬和 FMDV 复制，而 IRE1α 通路仅影响 FMDV 复制。进一步的研究表明，Sec62 在 FMDV 感染的后期阶段大量减少，并阻断了自噬相关的 IRE1α-JNK 通路的激活。此外，还发现 Sec62 促进 IRE1a 磷酸化，并负调控 FMDV 的增殖。重要的是，Sec62 可能与 LC3 相互作用，调节 ER 应激和自噬平衡，最终有助于 FMDV 与溶酶体融合而被清除。总之，这些结果表明，Sec62 通过激活 IRE1α-JNK 通路和将自噬体递送至溶酶体，是维持和恢复内质网稳态的关键分子，为 FMDV-宿主相互作用和新型抗病毒治疗提供了新的见解。
