The coronavirus E protein seems to contribute to the magnitude of the cytokine storm.137, 138 The SARS‐CoV E protein has ion channel activity and a postsynaptic density‐95/discs large/zone occludens‐1 (PDZ)‐binding motif (PBM). The PBM enables the E protein to interact with cellular proteins that contain PDZ domains. Of relevance to a cytokine storm, E protein has been shown to bind to the tandem PDZ domains of syntenin, resulting in constitutive activation of MAP kinases p38 in the signaling pathways that regulate the expression of inflammatory cytokines and hence, the overexpression of inflammatory cytokines.138 In addition, protein E's ion channel activity enables the E protein to form ion‐conductive pores in the planar lipid bilayers, causing cation imbalances, leading to the activation of NLR family pyrin domain containing 3 inflammasomes (NLRP3).137 The E protein of SARS‐CoV‐2 differs from that of SARS‐CoV by only one deletion and three amino acid substitutions, which are positioned in the flexible cytoplasmic regions, and are not expected to affect the protein structure, ion channel, or PBM function.139 Hence, it is highly plausible that SARS‐CoV‐2 E protein can trigger a cytokine storm that activates the inflammasome and inflammatory pathways, leading to increased edema in the lungs and ultimately ARDS.
Possible epigenetic dysregulation by SARS‐CoV‐2 proteinsAn analysis of the SARS‐CoV‐2 interactome provided evidence that several of the viral proteins (nsp5, nsp8, nsp13, E) interact with epigenetic and gene expression regulators145 (Figure 2). Nsp5 is associated with HDAC2. The transmembrane protein E interacted with the lysine acetylation readers, BRD2 and BRD4. Proteins involved in innate immune signaling interacted with viral proteins. TBK1 and TBK1 binding protein (TBKBP1) in the IFN pathway are associated with nsp13. RNF41/Nrdp1 interacted with nsp15, and translocase of outer mitochondrial membrane 70 (TOMM70) interacted with Orf9b. The viral proteins (nsp13, ORF9c) also target proteins in the NF‐κB pathway. The above interactions of the SARS‐CoV‐2 proteins could potentially disrupt epigenetic events and gene expression programming.
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