SERINC proteins potentiate antiviral type I IFN production and proinflammatory signaling pathways

Description The host restriction factor SERINC5 promotes intracellular innate signaling pathways to inhibit viral infection. Potentiating interferon responses The host restriction factor SERINC5 is found in the plasma membrane and is thought to inhibit HIV-1 infection through its incorporation into virions. Zeng et al. showed that upon viral infection of cells, SERINC5 also localized to mitochondria, where it interacted with the adaptor protein MAVS and promoted its oligomerization. Signaling downstream of MAVS led to activation of transcriptional regulators of the IRF and NF-κB families and the expression of genes encoding type I interferons (IFNs) and proinflammatory cytokines. KD of SERINC5 enhanced the replication of various viruses, suggesting that the potentiation of IFN and inflammatory cytokine signaling represents an additional antiviral response mediated by SERINC5. The SERINC (serine incorporator) proteins are host restriction factors that inhibit infection by HIV through their incorporation into virions. Here, we found that SERINC3 and SERINC5 exhibited additional antiviral activities by enhancing the expression of genes encoding type I interferons (IFNs) and nuclear factor κB (NF-κB) signaling. SERINC5 interacted with the outer mitochondrial membrane protein MAVS (mitochondrial antiviral signaling) and the E3 ubiquitin ligase and adaptor protein TRAF6, resulting in MAVS aggregation and polyubiquitylation of TRAF6. Knockdown of SERINC5 in target cells increased single-round HIV-1 infectivity, as well as infection by recombinant vesicular stomatitis virus (rVSV) bearing VSV-G or Ebola virus (EBOV) glycoproteins. Infection by an endemic Asian strain of Zika virus (ZIKV), FSS13025, was also enhanced by SERINC5 knockdown, suggesting that SERINC5 has direct antiviral activities in host cells in addition to the indirect inhibition mediated by its incorporation into virions. Further experiments suggested that the antiviral activity of SERINC5 was type I IFN–dependent. Together, these results highlight a previously uncharacterized function of SERINC proteins in promoting NF-κB inflammatory signaling and type I IFN production, thus contributing to its antiviral activities.

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