Shutdown of interferon signaling by a viral-hijacked E3 ubiquitin ligase

Abstract

Viruses have evolved a number of mechanisms to combat host antiviral responses in order to establish a pro-viral cellular environment. Many host antiviral responses rely on signaling cascades initiated by the production of IFN. Rotavirus, a pathogen known to infect nearly all known mammalian and avian animal species, employs NSP1 to counter IFN production. NSP1 proteins encoded by various rotavirus strains share little sequence conservation except for the presence of a putative N-terminal RING domain and a C-terminal substrate-targeting domain. While the targeting domain of most human and porcine rotavirus NSP1 proteins mediates the recruitment of β-TrCP, the targeting domain of many animal strains (simian, murine, equine, etc.) mediates the recruitment of IFN-regulatory factors (e.g., IRF-3/-7). NSP1 binding to β-TrCP or IRF proteins is correlated with proteasomal degradation of these targets in the infected cell.There is a growing body of data to suggest that NSP1 triggers the degradation of targets by hijacking a subset of E3 ubiquitin ligases: the cullin-RING ligases (CRLs). Hijacked CRLs are presumed to direct the ubiquitination and proteasomal degradation of NSP1-bound targets. CRLs are large modular complexes that are minimally comprised of a cullin scaffold protein (Cul1, 2, 3, 4a, 4b, 5, 7), a RING-domain containing protein (Rbx1, 2), and a substrate adaptor that directs the CRL to the target protein. Through multiple

Immune Ecosystem of Virus-Infected Host Tissues

“…Recently, tetherin has been shown to inhibit type I IFN via targeting MAVS [ 18 ]. A viral-hijacked E3 ubiquitin ligase is also shown to shut off IFN signaling [ 33 , 126 ]. A variety of IFNs subversion strategies by viruses have been extensively reported over the past 10 years [ 76 ].…”

Expression of Separate Heterologous Proteins from the Rotavirus NSP3 Genome Segment Using a Translational 2A Stop-Restart Element

“…Komoto et al also showed that it was possible to generate recombinant strains of SA11 rotavirus (rSA11) expressing Nluc luciferase, and EGFP and mCHERRY fluorescent proteins (FPs), by inserting sequences for these reporter genes immediately downstream of a 2A element within the NSP1 gene (22). Because the reporter sequences disrupted the ORF for the interferon antagonist NSP1, these viruses may lack the virulence of wildtype viruses (4,8).…”

Diverse and pivotal roles of neddylation in metabolism and immunity

“…MLN4924 treatment restored STAT2 expression in infected cells and elicited antiviral activity [180,200]. Rotavirus nonstructural protein NSP1 was reported to simultaneously interact with both CUL3 and b-TRCP and thereby assemble CRL3 to target b-TRCP for ubiquitination and subsequent degradation, leading to the inactivation of NF-jB to suppress host antiviral responses [201]. Sendi virus (SeV) infection led to the recruitment of IFN regulatory factor 3 (IRF3) to CRL1, followed by ubiquitination and degradation [202].…”