Possible role of the Nipah virus V protein in the regulation of the interferon beta induction by interacting with UBX domain-containing protein1

Abstract

Nipah virus (NiV) is a highly pathogenic paramyxovirus that causes lethal encephalitis in humans. We previously reported that the V protein, one of the three accessory proteins encoded by the P gene, is one of the key determinants of the pathogenesis of NiV in a hamster infection model. Satterfield B.A. et al. have also revealed that V protein is required for the pathogenicity of henipavirus in a ferret infection model. However, the complete functions of NiV V have not been clarified. In this study, we identified UBX domain-containing protein 1 (UBXN1), a negative regulator of RIG-I-like receptor signaling, as a host protein that interacts with NiV V. NiV V interacted with the UBX domain of UBXN1 via its proximal zinc-finger motif in the C-terminal domain. NiV V increased the level of UBXN1 protein by suppressing its proteolysis. Furthermore, NiV V suppressed RIG-I and MDA5-dependent interferon signaling by stabilizing UBXN1 and increasing the interaction between MAVS and UBXN1 in addition to directly interrupting the activation of MDA5. Our results suggest a novel molecular mechanism by which the induction of interferon is potentially suppressed by NiV V protein via UBXN1.

Regulation of MAVS Expression and Signaling Function in the Antiviral Innate Immune Response

“…During the later stages of viral infection, MAVS activity is negatively regulated by UBX-domain-containing protein 1 (UBXN1), a member of the ubiquitin-binding protein family. The expression of UBXN1 is strongly upregulated late during viral infection and it competes with TRAF3/TRAF6 for binding to MAVS (amino acids 455-460), thus blocking MAVS signaling (64,65). Gpatch domain-containing protein 3 (GPATCH3), a widely expressed protein, acts similarly to UBXN1.…”

“…HBX can promote recruitment of the E3 ubiquitin ligase linear ubiquitin chain assembly complex (LUBAC) to the mitochondria, and the subsequent linear ubiquitination of MAVS blocks MAVS-TRAF3 interactions (107). The V protein of Nipah virus inhibits degradation of the negative regulatory factor UBXN1, thereby enhancing blockade of MAVS-TRAF interactions by UBXN1 (65). Several viruses employ multiple strategies to antagonize antiviral immunity.…”

Nano-based approach to combat emerging viral (NIPAH virus) infection

“…41,47 This allows it to suppress expression of IFN α/β and antiviral gene at gene expression level and confirms lower probability of eliciting antiviral activity, than as happens in case of cytoplasmic inhibition by V proteins. 37,44,45 The cytoplasmic inhibitory activity of V proteins is achieved by its binding with dsRNA responding RLR receptor MAD5 hence down regulating the activation of TBK1 and IKKε which activates IFN α/β gene transcription factor IRF3 and IRF7 (Figure 3, D.1). This suppression of IFN β gene expression can be overcome by another TLR3 mediated alternative pathway by producing more amount of adaptor protein IRF1 which activates TBK1 ( Figure 3, B.1).…”

V protein, the virulence factor across the family Paramyxoviridae: a review

“…Besides, the C termini of the V protein for these two viruses were found to interact with the helicase domain of MDA-5 as well to suppress the IFN-β transcription Childs et al, 2007). The ability of NiV to suppress RIG-I and MDA5-dependent interferon signalling is defined by the stabilisation of a regulator namely UBX domain-containing protein 1 (UBXN1) by the V protein (Uchida et al, 2018).…”