PDF(Pubmed)
Abstract：
The STimulator of INterferon Genes (STING) constitutes a major DNA-sensing pathway that restricts HSV-1 infection in different models by activating type I interferon and pro-inflammatory responses. To counteract STING, HSV-1 has evolved numerous strategies including mechanisms to interfere with its oligomerization, post-translational modifications, and downstream signaling. Previously, we demonstrated that STING is packaged in extracellular vesicles (EVs) produced from HSV-1-infected cells. These EVs activated antiviral responses in uninfected recipient cells and suppressed a subsequent HSV-1 infection in a STING-dependent manner. Here, we provide information on the packaging of STING in EVs and its exocytosis. We found that STING exocytosis did not occur in CD63 knockdown cells supporting that STING follows the CD63 exocytosis pathway. Consistently, we found that STING co-localized with CD63 in cytoplasmic globular structures and exosomal STING and CD63 co-fractionated. Both golgicide A and brefeldin A prevented STING exocytosis during HSV-1 infection suggesting that STING trafficking through the Golgi is required. A STING ligand was insufficient for STING exocytosis, and downstream signaling through TBK1 was not required. However, STING palmitoylation and tethering to the ER by STIM1 were required for STING exocytosis. Finally, we found that HSV-1 replication/late gene expression triggered CD63 exocytosis that was required for STING exocytosis. Surprisingly, HSV-2 strain G did not trigger CD63 or STING exocytosis as opposed to VZV and HCMV. Also, EVs from HSV-1(F)- and HSV-2(G)-infected cells displayed differences in their ability to restrict these viruses. Overall, STING exocytosis is induced by certain viruses and shapes the microenvironment of infection.IMPORTANCEExtracellular vesicles (EVs) are released by all types of cells as they constitute a major mechanism of intercellular communication. The packaging of specific cargo in EVs and the pathway of exocytosis are not fully understood. STING is a sensor of a broad spectrum of pathogens and a key component of innate immunity. STING exocytosis during HSV-1 infection has been an intriguing observation, raising questions of whether this is a virus-induced process, the purpose it serves, and whether it is observed after infection with other viruses. Here, we have provided insights into the pathway of STING exocytosis and determined factors involved. STING exocytosis is a virus-induced process and not a response of the host to the infection. Besides HSV-1, other herpes viruses triggered STING exocytosis, but HSV-2(G) did not. HSV-1 EVs displayed different restriction capabilities compared with HSV-2(G) EVs. Overall, STING exocytosis is triggered by viruses to shape the microenvironment of infection.
摘要：
INterferon基因的刺激器（STING）构成了主要的DNA传感途径，该途径通过激活I型干扰素和促炎反应来限制不同模型中的HSV-1感染。为了抵消STING，HSV-1已经发展了许多策略，包括干扰其低聚的机制，翻译后修饰，和下游信令。以前,我们证明STING包装在由HSV-1感染的细胞产生的细胞外囊泡(EV)中。这些EV在未感染的受体细胞中激活抗病毒反应，并以STING依赖性方式抑制随后的HSV-1感染。这里,我们提供有关电动汽车中STING包装及其胞吐的信息。我们发现STING胞吐作用不发生在CD63敲低细胞中，支持STING遵循CD63胞吐作用途径。始终如一，我们发现STING与CD63共定位在细胞质球状结构中，并且外泌体STING和CD63共分离。golgicideA和brefeldinA均可预防HSV-1感染期间的STING胞吐作用，这表明STING需要通过高尔基体运输。STING配体不足以进行STING胞吐，并且不需要通过TBK1的下游信令。然而,STING棕榈酰化和STIM1与ER的束缚是STING胞吐作用所必需的。最后,我们发现HSV-1复制/晚期基因表达触发了STING胞吐所需的CD63胞吐作用.令人惊讶的是,与VZV和HCMV相反,HSV-2菌株G不触发CD63或STING胞吐作用。此外，来自HSV-1（F）和HSV-2（G）感染的细胞的EV在限制这些病毒的能力方面表现出差异。总的来说,STING胞吐作用由某些病毒诱导并形成感染的微环境。重要细胞外囊泡（EV）由所有类型的细胞释放，因为它们构成了细胞间通讯的主要机制。电动汽车中特定货物的包装和胞吐途径尚未完全了解。STING是广谱病原体的传感器和先天免疫的关键组成部分。在HSV-1感染期间STING胞吐作用是一个有趣的观察结果，提出了这是否是病毒诱导的过程的问题，它所服务的目的，以及是否在感染其他病毒后观察到。这里,我们提供了对STING胞吐作用途径的见解和确定的相关因素。STING胞吐作用是病毒诱导的过程，而不是宿主对感染的反应。除了HSV-1，其他疱疹病毒引发STING胞吐作用，但HSV-2（G）没有。与HSV-2（G）EV相比，HSV-1EV显示出不同的限制能力。总的来说,STING胞吐作用是由病毒触发的，以塑造感染的微环境。
