Protein disulfide isomerases (PDIs) negatively regulate ebolavirus structural glycoprotein expression in the endoplasmic reticulum (ER) via the autophagy-lysosomal pathway

文献类型： 外文期刊

第一作者： Wang, Bin

作者： Wang, Bin;Zhang, Jing;Liu, Xin;Lu, Xiaoran;Yao, Xiaoyu;Zheng, Yong-Hui;Wang, Bin;Liu, Xin;Chai, Qingqing;Johnson, Silas F.;Schwartz, Richard C.;Zheng, Yong-Hui;Yang, Zhichang;Sun, Liangliang

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关键词： Autophagy; ebola; ERAD; ERp57; ER-phagy; EVD; filoviruses; glycoproteins; lysosomes; reticulophagy

期刊名称：AUTOPHAGY （ 影响因子：13.391； 五年影响因子：16.142 ）

ISSN： 1554-8627

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收录情况： SCI

摘要： Zaire ebolavirus (EBOV) causes a severe hemorrhagic fever in humans and non-human primates with high morbidity and mortality. EBOV infection is dependent on its structural glycoprotein (GP), but high levels of GP expression also trigger cell rounding, detachment, and downregulation of many surface molecules that is thought to contribute to its high pathogenicity. Thus, EBOV has evolved an RNA editing mechanism to reduce its GP expression and increase its fitness. We now report that the GP expression is also suppressed at the protein level in cells by protein disulfide isomerases (PDIs). Although PDIs promote oxidative protein folding by catalyzing correct disulfide formation in the endoplasmic reticulum (ER), PDIA3/ERp57 adversely triggered the GP misfolding by targeting GP cysteine residues and activated the unfolded protein response (UPR). Abnormally folded GP was targeted by ER-associated protein degradation (ERAD) machinery and, unexpectedly, was degraded via the macroautophagy/autophagy-lysosomal pathway, but not the proteasomal pathway. PDIA3 also decreased the GP expression from other ebolavirus species but increased the GP expression from Marburg virus (MARV), which is consistent with the observation that MARV-GP does not cause cell rounding and detachment, and MARV does not regulate its GP expression via RNA editing during infection. Furthermore, five other PDIs also had a similar inhibitory activity to EBOV-GP. Thus, PDIs negatively regulate ebolavirus glycoprotein expression, which balances the viral life cycle by maximizing their infection but minimizing their cellular effect. We suggest that ebolaviruses hijack the host protein folding and ERAD machinery to increase their fitness via reticulophagy during infection.

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