Abstract
Following the outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, the novel coronavirus SARS-CoV-2 emerged at the end of 2019. SARS-CoV-2 is a highly infectious pathogen that rapidly spread around the world causing the worst pandemic in the past 100 years. SARS-CoV-2 shares high sequence homology with SARS-CoV and causes coronavirus disease 2019 (COVID-19), leading to pneumonia and severe acute respiratory distress syndrome. Although probably not as lethal as SARS-CoV, its robust transmissibility by asymptomatic individuals is an important contributor to the pandemic. Like other betacoronaviruses, SARS-CoV-2 encodes four major structural proteins: spike (S), membrane (M), nucleocapsid (N) and envelope (E). SARS-CoV E protein is abundant in infected cells and plays a crucial role in viral particle assembly. Moreover, the E proteins of SARS coronaviruses likely have important roles in pathogenesis by manipulating a number of cellular processes. Thus, SARS-CoV-2 E protein could also be a critical virulence factor. Ectopic expression of SARS-CoV E was reported to trigger apoptotic cell death of T lymphocytes, which could potentially contribute to the lymphopenia observed in fatal cases, though a causal association is unproven. A potential mechanism for inducing apoptosis was reported to involve an interaction between a putative Bcl-2 homology 3 (BH3)-like motif in SARS-CoV E and the anti-apoptotic host protein Bcl-xL. Here we provide the first computational evidence indicating that both the SARS-CoV E and SARS-CoV-2 E have a C-terminal BH3-like motif. We used available sequence data for SARS-CoV-2 and related coronaviruses combined with structural information to evaluate the structure to biological activity relationships of the SARS-CoV-2 E BH3-like motif. Our analysis reveals a predicted interactome for E that is extensively wired to the Bcl-2 apoptotic switch that could potentially be a therapeutic target. Last, network reconstruction identified both the BH3-binding protein Bcl-xL and the autophagy effector Beclin 1, another BH3-containing protein, as vulnerable nodes in the host cellular defense system against SARS-CoV-2.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Author list was updated. Abstract updated. Results and Discussion section was completed. Methods were completed. Figure 1, Figure 2 and Figure 5 modified. Novel Figure 7 added. Supplemental files uploaded.
