HIV-1 restriction by SERINC5

Abstract

Serine incorporator 5 (SERINC5 or SER5) is a multipass transmembrane protein with ill-defined cellular activities. SER5 was recently described as a human immunodeficiency virus 1 (HIV-1) restriction factor capable of inhibiting HIV-1 that does not express its accessory protein Nef (Δ Nef). SER5 incorporated into the viral membrane impairs the entry of HIV-1 by disrupting the fusion between the viral and the plasma membrane after envelope receptor interaction induced the first steps of the fusion process. The mechanisms of how SER5 prevents membrane fusion are not fully understood and viral envelope proteins were identified that escape the SER5-mediated restriction. Primate lentiviruses, such as HIV-1 and simian immunodeficiency viruses (SIVs), use their accessory protein Nef to downregulate SER5 from the plasma membrane by inducing an endocytic pathway. In addition to being directly antiviral, recent data suggest that SER5 is an important adapter protein in innate signaling pathways leading to the induction of inflammatory cytokines. This review discusses the current knowledge about HIV-1 restriction by SER5.

Keywords: HIV-1; Nef; Restriction factors; SERINC5.

Fig. 1

Model of IFN-1 and inflammatory pathways induced by SER5 according Zeng et al. [50]. After the viral infection by Sendai virus or the stimulation with poly (I:C) or LPS, SER5 relocates from the plasma membrane to the mitochondrial membrane. SER5 associates with the transmembrane domains of the mitochondrial membrane protein MAVS and with the E3 ubiquitin ligase TRAF6. TRAF6 associates also with MAVS. This stable complex is the result of the MAVS aggregation and the polyubiquitination of TRAF6. This complex could have three effects (1) the activation of the canonical NF-κB pathway: after the phosphorylation of the IκBα repressor, the complex p50/p56 (p65 also named RelA) is transported to the nucleus and induces the expression of pro-inflammatory genes like ISG15, TNF-α IL-6; (2) the activation of the non-canonical NF-κB pathway; and (3) the phosphorylation of IRF3 and the translocation of phosphorylated dimers to the nucleus to induce the activation expression of IFN-I

Fig. 2

Model of the effect of IFN-I on SER5. Type I interferon increases the amount of SER5 in the plasma membrane by reducing its recycling or endocytosis. This effect can be antagonized by ruxolitinib, which inhibits the Jak/STAT signalization pathway. This IFN effect is not dependent on the modulation of mRNA or protein levels of SER5 [51]

Fig. 3

HIV-1 counteracts the antiviral activity of SER5 by its Nef protein.. When Nef is absent, the surface expression of SER5 in the plasma membrane is not altered and SER5 is incorporated into the newly formed viral particle. The infectivity of the virus will depend on its envelope. Virions with a SER5-sensitive envelope have an impaired infectivity while a resistant envelope allows the infection of the target cell even in the presence of SER5. If Nef is present, SER5 associates with the AP-2 complex and Nef with low affinity. Afterwards, Cyclin K/CDK13 is recruited and phosphorylates SER5 in the intracellular loop 4 (ICL4). In consequence, the AP-2 complex is recruited which induces the endogenization of SER5 to Rab7 + late endosomes, SER5 is downregulated from the plasma membrane and thus is not incorporated into the budding virion keeping its infectivity capacity [55]