Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Center for Microbial Pathogenesis, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
J Virol. 2020 Apr 16;94(9). doi: 10.1128/JVI.00029-20.
Flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), rely heavily on the availability of endoplasmic reticulum (ER) membranes throughout their life cycle, and degradation of ER membranes restricts flavivirus replication. Accordingly, DENV and ZIKV restrict ER turnover by protease-mediated cleavage of reticulophagy regulator 1 (RETREG1), also known as FAM134B, an autophagy receptor responsible for targeted ER sheet degradation. Given that the induction of autophagy may play an important role in flavivirus replication, the antiviral role of RETREG1 suggests that specialized autophagic pathways may have differential effects on the flavivirus life cycle. We previously identified BPI fold-containing family B member 3 (BPIFB3) as a regulator of autophagy that negatively controls enterovirus replication. Here, we show that in contrast to enteroviruses, BPIFB3 functions as a positive regulator of DENV and ZIKV infection and that its RNA interference-mediated silencing inhibits the formation of viral replication organelles. Mechanistically, we show that depletion of BPIFB3 enhances RETREG1-dependent reticulophagy, leading to enhanced ER turnover and the suppression of viral replication. Consistent with this, the antiviral effects of BPIFB3 depletion can be reversed by RETREG1 silencing, suggesting a specific role for BPIFB3 in regulating ER turnover. These studies define BPIFB3 as a required host factor for both DENV and ZIKV replication and further contribute to our understanding of the requirements for autophagy during flavivirus infection. Flaviviruses and other arthropod-transmitted viruses represent a widespread global health problem, with limited treatment options currently available. Thus, a better understanding of the cellular requirements for their infection is needed. Both DENV and ZIKV rely on expansion of the endoplasmic reticulum (ER) and the induction of autophagy to establish productive infections. However, little is known regarding the interplay between the requirements for autophagy initiation during infection and the mechanisms used by these viruses to avoid clearance through the autophagic pathway. Our study highlights the importance of the host factor BPIFB3 in regulating flavivirus replication and further confirms that the RETREG1-dependent reticulophagy pathway is antiviral to both DENV and ZIKV.
黄病毒，包括登革热病毒（DENV）和寨卡病毒（ZIKV），在其生命周期中严重依赖内质网（ER）膜的可用性，而 ER 膜的降解限制了黄病毒的复制。因此，DENV 和 ZIKV 通过蛋白酶介导的对自噬受体 RETREG1（也称为 FAM134B）的切割来限制 ER 周转率，该受体负责靶向 ER 片层降解。鉴于自噬的诱导可能在黄病毒复制中发挥重要作用，RETREG1 的抗病毒作用表明，专门的自噬途径可能对黄病毒生命周期产生不同的影响。我们之前发现 BPI 折叠家族 B 成员 3（BPIFB3）是一种自噬调节剂，可负调控肠道病毒复制。在这里，我们表明，与肠道病毒相反，BPIFB3 是 DENV 和 ZIKV 感染的正调节剂，其 RNA 干扰介导的沉默抑制病毒复制细胞器的形成。在机制上，我们表明，BPIFB3 的耗竭增强了依赖于 RETREG1 的网质体自噬，导致 ER 周转率增加和病毒复制受到抑制。与此一致，BPIFB3 耗竭的抗病毒作用可以通过 RETREG1 沉默逆转，表明 BPIFB3 在调节 ER 周转率方面具有特定作用。这些研究将 BPIFB3 定义为 DENV 和 ZIKV 复制所必需的宿主因子，并进一步促进了我们对黄病毒感染期间自噬要求的理解。黄病毒和其他节肢动物传播的病毒是一个广泛存在的全球健康问题，目前可用的治疗方法有限。因此，需要更好地了解它们感染的细胞要求。DENV 和 ZIKV 都依赖于内质网（ER）的扩张和自噬的诱导来建立有性感染。然而，对于感染期间自噬起始的要求以及这些病毒用于避免通过自噬途径清除的机制知之甚少。我们的研究强调了宿主因子 BPIFB3 在调节黄病毒复制中的重要性，并进一步证实了依赖于 RETREG1 的网质体自噬途径对 DENV 和 ZIKV 均具有抗病毒作用。
