The host restriction factor SERINC5 inhibits HIV-1 transcription by negatively regulating NF-κB signaling.

Serine incorporator 5 (SER5) can be incorporated into HIV-1 virions to block viral entry by disrupting the envelope glycoprotein-mediated viral fusion to the plasma membrane. Recent studies suggest that SER5 also inhibits HIV-1 mRNA transcription and the subsequent progeny virion biogenesis. However, the underlying mechanisms through which SER5 antagonizes the viral transcription remain poorly understood. Here, we demonstrate that SER5 inhibits HIV-1 transcription by negatively regulating NF-κB signaling, which is mediated by the retinoic acid-inducible gene I-like receptors, MDA5 and RIG-I. By recruiting TRIM40 as the E3 ubiquitination ligase to promote K48-linked polyubiquitination and proteasomal degradation of MDA5 and RIG-I, SER5 impedes nuclear translocation of the p50/p65 dimer, resulting in repression of HIV-1 LTR-driven gene expression. Hence, our findings strongly support a role for SER5 in restricting HIV-1 replication through inhibition of NF-κB-mediated viral gene expression.