Protein Disulfide Isomerases Negatively Regulate Ebolavirus Structural Glycoprotein Expression

Ebola viruses (EBOV) express cytotoxic structural glycoprotein GP1,2 to mediate virus entry. To explore a novel viral fitness mechanism, we used mass spectrometry to investigate how EBOV-GP1,2 expression is regulated in the endoplasmic reticulum (ER). We found that ER protein 57 (ERp57), a member of protein disulfide isomerases (PDIs) that promote protein folding, targets EBOV-GP1,2 cysteine residues required for correct cross-linking, thus adverselytriggering misfolding, which in turn activates the unfolded protein response. Misfolded EBOV-GP1,2 is targeted by ER-associated protein degradation machinery and, unexpectedly, is degraded in lysosomes via autophagosomes, but not proteasomes. Five other PDIs also have similar inhibitory activity. In contrast, the expression of Marburg virus and some other enveloped virus glycoproteins is increased by ERp57. Thus, PDIs can negatively regulate EBOV glycoprotein expression, which enables optimum viral infectivity and minimizes cytotoxicity. Importantly, PDIs emerge as potential targets for inhibition of Ebola virus infection.