Role of Severe Acute Respiratory Syndrome Coronavirus Viroporins E, 3a, and 8a in Replication and Pathogenesis

Abstract

Viroporins are viral proteins with ion channel (IC) activity that play an important role in several processes, including virus replication and pathogenesis. While many coronaviruses (CoVs) encode two viroporins, severe acute respiratory syndrome CoV (SARS-CoV) encodes three: proteins 3a, E, and 8a. Additionally, proteins 3a and E have a PDZ-binding motif (PBM), which can potentially bind over 400 cellular proteins which contain a PDZ domain, making them potentially important for the control of cell function. In the present work, a comparative study of the functional motifs included within the SARS-CoV viroporins was performed, mostly focusing on the roles of the IC and PBM of E and 3a proteins. Our results showed that the full-length E and 3a proteins were required for maximal SARS-CoV replication and virulence, whereas viroporin 8a had only a minor impact on these activities. A virus missing both the E and 3a proteins was not viable, whereas the presence of either protein with a functional PBM restored virus viability. E protein IC activity and the presence of its PBM were necessary for virulence in mice. In contrast, the presence or absence of the homologous motifs in protein 3a did not influence virus pathogenicity. Therefore, dominance of the IC and PBM of protein E over those of protein 3a was demonstrated in the induction of pathogenesis in mice.

Porcine deltacoronavirus (PDCoV) modulates calcium influx to favor viral replication

“…activity (Surya et al, 2015;Verdia-Baguena et al, 2013). In addition, some accessory proteins of CoVs, such as SARS-CoV 3a and 8a, the human coronavirus 229E (HCoV-229E) 4a protein and the porcine epidemic diarrhea virus (PEDV) ORF3, have been identified as viroporins (Castano-Rodriguez et al, 2018;Wang et al, 2012;Zhang et al, 2014). PDCoV also encodes an E protein and three accessory proteins (NS6, NS7 and NS7a) (Fang et al, , 2017.…”

Viroporins and inflammasomes: A key to understand virus-induced inflammation

“…They could possibly be responsible for inflammasome activation [49,96]. It was recently shown that the SARS 3a protein activates the NLRP3 inflammasome in lipopolysaccharide-primed macrophages by affecting K + efflux and mitochondrial reactive oxygen species [93].…”

PDZ Domains as Drug Targets

“…[259] By binding to the E6AP ubiquitin ligase, HPV E6 targets p53 and the PDZ domain proteins for degradation (Figure 12a). [265] In Kaposi's sarcoma herpesvirus, expression of the PDZ-LIM domain-containing protein 2 gene (PDLIM2) is repressed, which enables tumorigenesis and tumor maintenance in infected cells. While HPV protein E6 has been shown to interact with p53 and E6AP in both low and high-risk HPVs, [260,261] only the high-risk cancer-causing HPV E6 proteins contain a C-terminal PDZ binding motif, which is recognized by different PDZ domain proteins depending on the HPV strain.…”