FIG 7.

SAMHD1 inhibits signal transduction mediated by the TRAF6-TAK1 complex during HIV-1 infection or cytokine stimulation. Cytoplasmic SAMHD1 suppresses the NF-κB and p38 MAPK pathways, which are activated through signaling cascades that branch from the TRAF6-TAK1 axis. SAMHD1 inhibits phosphorylation of the IκBα and p38 proteins induced by cytokine stimulation (IL-1β) or recognition of pathogen-associated molecular patterns (LPS) by cells, as well as NF-κB-mediated gene expression by reducing TNF-α mRNA synthesis. SAMHD1 suppresses innate immune responses to HIV-1 infection through negative modulation of TRAF6-TAK1 signaling, as SAMHD1-deficient cells infected with HIV-1 show enhanced production of viral mRNA transcripts, which is reduced by TRAF6 silencing or pharmacological inhibition of TAK1. For simplicity, only cytoplasmic SAMHD1 is shown. The letter p in red indicates phosphorylation.