IDENTIFICATION OF PSGL-1 AND THE SHREK FAMILY OF PROTEINS AS BROAD-SPECTRUM ANTIVIRAL HOST FACTORS
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PSGL-1 (P-selectin glycoprotein ligand-1) is a dimeric, mucin-like glycoprotein with a molecular weight of 120 kDa and functions as a ligand for P-, E-, and L-selectins. PSGL- 1 is predominantly expressed on the surface of myeloid cells and lymphoid cells and is up-regulated during inflammation to mediate leukocyte tethering and rolling on the endothelium's surface for migration into inflamed tissues. Previous work has reported that PSGL-1 expression restricts HIV-1 infectivity. However, the mechanism by which PSGL-1 inactivates HIV-1 infectivity remained elusive. Here, we demonstrated that PSGL-1 inhibits HIV-1 particle infectivity by incorporating into assembling virion particles and subsequently preventing virus particle binding to target cells through steric hindrance. The anti-HIV effect of PSGL-1 occurred irrespectively of receptor usage; particles bearing either the HIV-1 envelope glycoprotein, the vesicular stomatitis virus G (VSV-G) glycoprotein, or completely lacking viral glycoproteins were all impaired in xii their ability to bind target cells. Mutational mapping revealed that the extracellular domain of PSGL-1 is required for its anti–HIV-1 activity, while the cytoplasmic domain slightly contributed to virus inhibition. Additionally, we found that PSGL-1 inhibits the infectivity of other enveloped viruses including murine leukemia virus and influenza A virus, indicating that PSGL-1 is a host factor with broad-spectrum antiviral activity. We also tested a panel of mucins and mucin-like molecules that share structural features with PSGL-1(CD43, TIM-1, CD34, PODXL1, PODXL2, CD164, MUC1, MUC4, and TMEM123). We found these proteins also inactivated HIV-1 infectivity. We demonstrated that, like PSGL-1, these mucin domain-containing proteins block HIV-1 infectivity by inhibiting virus particle attachment to target cells. Based on their shared structural characteristics and antiviral activity, we have named these proteins the Surface- Hinged, Rigidly Extended Killer (SHREK) family of virion inactivators. Besides inhibiting HIV-1, the proteins tested blocked infection by the influenza A virus and a subset of them inhibited the infectivity of a hybrid alphavirus-SARS-CoV-2 (HaCoV2) pseudovirus, demonstrating that SHREK proteins are broad-spectrum host antiviral factors. Collectively, these results suggest that SHREK proteins may be a part of host innate immunity against enveloped viruses.