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.
Highlights
Nipah virus (NiV) is an emerging zoonotic virus which belongs to the genus Henipavirus in the family Paramyxoviridae, and was first identified as the pathogen that caused an outbreak of fatal encephalitis in humans in Malaysia and Singapore in 19991,2
Our results showed that ubiquitin regulatory X (UBX) domain-containing protein 1 (UBXN1) increased the suppression activity of NiV V on MDA5 activation, and conferred the suppression activity on RIG-I activation to NiV V
These results potentially suggest a novel molecular mechanism for the suppression of IFN induction, in which NiV V stabilizes the negative regulator of RIG-I-like receptor signaling, UBXN1
Summary
Nipah virus (NiV) is an emerging zoonotic virus which belongs to the genus Henipavirus in the family Paramyxoviridae, and was first identified as the pathogen that caused an outbreak of fatal encephalitis in humans in Malaysia and Singapore in 19991,2. Previous studies have demonstrated that henipavirus V proteins suppress the host antiviral response by targeting multiple host proteins. Henipavirus V proteins interact with LGP2 to suppress the RIG-I-dependent induction of IFN21. V proteins of NiV and HeV interacts with signal transducer and activator of transcription 1 and 2 (STAT1 and STAT2) in IFN-responsive signaling pathway, through its N-terminal domain, which it shares with the P and W proteins, and prevents their activation and nuclear accumulation[24,25]. NiV V negatively regulates minigenome replication[26] These reports have revealed that V protein interacts with multiple host proteins to contribute to the severe pathogenicity of henipavirus, and to elucidate the unknown molecular mechanism underlying the pathogenicity of henipavirus, the host molecule interacting with henipavirus V proteins should be further investigated. We analyzed the effects of the interaction between NiV V and UBXN1
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