PSGL-1 is an evolutionarily conserved antiviral restriction factor.

The arms race between viruses and their hosts shaped the evolutionary history and the genome composition of both parties. Restriction factors are the first-line antiviral effectors encoded by the host genomes and are often conserved through evolution to protect the hosts from morbidity, mortality, and even extinction associated with viral infections. There are a number of restriction factors identified so far to counteract HIV infection of the humans. PSGL-1 is a recently characterized human restriction factor that acts both early and late in the viral life cycle, the latter of which is antagonized by the HIV-1 Vpu protein. Here we show and in a knockout mouse model that PSGL-1's antiviral function is conserved in mice for combating the murine leukemia virus (MLV). In counter-strike, the glycogag or glycoMA proteins encoded by MLV can interact with mouse PSGL-1, which leads to Cul3-KLHL20 E3 ligase-dependent ubiquitination and degradation of PSGL-1. The amino acids involved in this interaction demonstrate the evidence of positive selection, manifesting the evolution pressure from the antagonism between PSGL-1 and glycogag/glycoMA. Our data support that PSGL-1 is an evolutionarily conserved antiviral restriction factor. IMPORTANCE Studying the co-evolution between viruses and humans is important for understanding why we are what we are now as well as for developing future antiviral drugs. Here we pinned down an evolutionary arms race between retroviruses and mammalian hosts at the molecular level by identifying the antagonism between a host antiviral restriction factor PSGL-1 and viral accessory proteins. We show that this antagonism is conserved from mouse to human and from mouse retrovirus to HIV. Further studying this antagonism might provide opportunities for developing new antiviral therapies.