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.IMPORTANCE 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.

中文翻译：

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BPIFB3调节内质网形态，以促进黄病毒复制。

包括登革热病毒（DENV）和寨卡病毒（ZIKV）在内的黄病毒在整个生命周期中都严重依赖内质网（ER）膜的可用性，而ER膜的降解会限制黄病毒的复制。因此，DENV和ZIKV通过蛋白酶介导的网状调节因子1（RETREG1）（也称为FAM134B，一种负责靶向ER片降解的自噬受体）来限制ER的转换。鉴于自噬的诱导可能在黄病毒复制中起重要作用，RETREG1的抗病毒作用表明专门的自噬途径可能对黄病毒的生命周期产生不同的影响。我们之前确定了包含BPI折叠的B族3成员（BPIFB3）作为自噬的调节剂，可负面控制肠病毒的复制。这里，我们表明，与肠病毒相反，BPIFB3充当DENV和ZIKV感染的正调节剂，其RNA干扰介导的沉默抑制了病毒复制细胞器的形成。从机理上讲，我们表明BPIFB3的耗竭增强了RETREG1依赖的网状组织，导致增强的ER营业额和病毒复制的抑制。与此相一致，RETREG1沉默可逆转BPIFB3耗竭的抗病毒作用，表明BPIFB3在调节ER周转中起特定作用。这些研究将BPIFB3定义为DENV和ZIKV复制的必需宿主因子，并进一步有助于我们理解黄病毒感染期间自噬的要求。重要黄病毒和其他节肢动物传播的病毒代表了广泛的全球健康问题，目前只有有限的治疗选择。因此，需要更好地了解细胞对其感染的需求。DENV和ZIKV都依靠内质网（ER）的扩展和自噬的诱导来建立生产性感染。然而，关于感染期间自噬启动的要求与这些病毒避免通过自噬途径清除的机制之间的相互作用的了解甚少。我们的研究突出了宿主因子BPIFB3在调节黄病毒复制中的重要性，并进一步证实了依赖RETREG1的网状细胞通路对DENV和ZIKV均具有抗病毒性。DENV和ZIKV都依靠内质网（ER）的扩展和自噬的诱导来建立生产性感染。然而，关于感染期间自噬启动的要求与这些病毒避免通过自噬途径清除的机制之间的相互作用的了解甚少。我们的研究突出了宿主因子BPIFB3在调节黄病毒复制中的重要性，并进一步证实了依赖RETREG1的网状细胞通路对DENV和ZIKV均具有抗病毒性。DENV和ZIKV都依靠内质网（ER）的扩展和自噬的诱导来建立生产性感染。但是，关于感染期间自噬引发的要求与这些病毒避免通过自噬途径清除的机制之间的相互作用的了解甚少。我们的研究突出了宿主因子BPIFB3在调节黄病毒复制中的重要性，并进一步证实了依赖RETREG1的网状细胞通路对DENV和ZIKV均具有抗病毒性。关于感染过程中自噬启动的要求与这些病毒避免通过自噬途径清除的机制之间的相互作用尚不清楚。我们的研究突出了宿主因子BPIFB3在调节黄病毒复制中的重要性，并进一步证实了依赖RETREG1的网状细胞通路对DENV和ZIKV均具有抗病毒性。关于感染过程中自噬启动的要求与这些病毒避免通过自噬途径清除的机制之间的相互作用尚不清楚。我们的研究突出了宿主因子BPIFB3在调节黄病毒复制中的重要性，并进一步证实了依赖RETREG1的网状细胞通路对DENV和ZIKV均具有抗病毒性。