在与溶酶体融合后,自噬吞噬双膜结合自噬体中的细胞成分以清除和再循环。因此,自噬是维持蛋白质稳定和强大的细胞内在宿主防御机制的关键过程,通过一种称为异种吞噬的选择性自噬的特定形式来保护细胞免受病原体的侵害。在这种情况下,泛素化作为自噬受体识别货物的信号,将它们引向自噬体用于随后的分解。然而,自噬可以发挥双重作用,因为包括正疱疹病毒科成员在内的许多病毒可以抑制或利用自噬以获得自身利益并在宿主细胞内复制。越来越多的证据表明单纯疱疹病毒1型(HSV-1),一种高度流行的人类病原体,感染表皮角质形成细胞和敏感神经元,能够负向调节自噬。由于HSV-1感染对自噬受体的影响研究甚少,本研究旨在了解HSV-1生产性感染对参与异种吞噬的主要自噬受体水平的影响,细胞内病原体募集到自噬体中的关键蛋白质。我们发现,人类神经胶质瘤细胞和角质形成细胞中的生产性HSV-1感染导致Ub缀合物的总水平降低,并降低自噬受体的蛋白质水平,包括SQSTM1/p62,OPTN1,NBR1和NDP52,这种表型也伴随着LC3-I和LC3-II水平的降低,直接与自噬受体相互作用。机械上,我们显示这些表型是在生产性HSV-1感染的早期阶段异种吞噬激活以限制病毒复制的结果,从而降低后代HSV-1产量。此外,我们发现去除外皮HSV-1蛋白US11,这是一种公认的抵抗宿主细胞自噬的病毒因子,增强自噬受体的清除,子代HSV-1产量显着降低。此外,US11的去除增加了SQSTM1/p62的泛素化,表明US11减缓了自噬受体的自噬周转.总的来说,我们的研究结果表明,异种吞噬是针对HSV-1复制的有效宿主防御,并揭示了自噬受体在通过异种吞噬将HSV-1递送至清除过程中的作用.
Autophagy engulfs cellular components in double-membrane-bound autophagosomes for clearance and recycling after fusion with lysosomes. Thus, autophagy is a key process for maintaining proteostasis and a powerful cell-intrinsic host defense mechanism, protecting cells against pathogens by targeting them through a specific form of selective autophagy known as xenophagy. In this context, ubiquitination acts as a signal of recognition of the cargoes for autophagic receptors, which direct them towards autophagosomes for subsequent breakdown. Nevertheless, autophagy can carry out a dual role since numerous viruses including members of the Orthoherpesviridae family can either inhibit or exploit autophagy for its own benefit and to replicate within host cells. There is growing evidence that Herpes simplex virus type 1 (HSV-1), a highly prevalent human pathogen that infects epidermal keratinocytes and sensitive neurons, is capable of negatively modulating autophagy. Since the effects of HSV-1 infection on autophagic receptors have been poorly explored, this study aims to understand the consequences of HSV-1 productive infection on the levels of the major autophagic receptors involved in xenophagy, key proteins in the recruitment of intracellular pathogens into autophagosomes. We found that productive HSV-1 infection in human neuroglioma cells and keratinocytes causes a reduction in the total levels of Ub conjugates and decreases protein levels of autophagic receptors, including SQSTM1/p62, OPTN1, NBR1, and NDP52, a phenotype that is also accompanied by reduced levels of LC3-I and LC3-II, which interact directly with autophagic receptors. Mechanistically, we show these phenotypes are the result of xenophagy activation in the early stages of productive HSV-1 infection to limit virus replication, thereby reducing progeny HSV-1 yield. Additionally, we found that the removal of the tegument HSV-1 protein US11, a recognized viral factor that counteracts autophagy in host cells, enhances the clearance of autophagic receptors, with a significant reduction in the progeny HSV-1 yield. Moreover, the removal of US11 increases the ubiquitination of SQSTM1/p62, indicating that US11 slows down the autophagy turnover of autophagy receptors. Overall, our findings suggest that xenophagy is a potent host defense against HSV-1 replication and reveals the role of the autophagic receptors in the delivery of HSV-1 to clearance via xenophagy.