Abstract
Mucins and mucin-like molecules are highly glycosylated, high-molecular-weight cell surface proteins that possess a semi-rigid and highly extended extracellular domain. P-selectin glycoprotein ligand-1 (PSGL-1), a mucin-like glycoprotein, has recently been found to restrict HIV-1 infectivity through virion incorporation that sterically hinders virus particle attachment to target cells. Here, we report the identification of a family of antiviral cellular proteins, named the Surface-Hinged, Rigidly-Extended Killer (SHREK) family of virion inactivators (PSGL-1, CD43, TIM-1, CD34, PODXL1, PODXL2, CD164, MUC1, MUC4, and TMEM123) that share similar structural characteristics with PSGL-1. We demonstrate that SHREK proteins block HIV-1 infectivity by inhibiting virus particle attachment to target cells. In addition, we demonstrate that SHREK proteins are broad-spectrum host antiviral factors that block the infection of diverse viruses such as influenza A. Furthermore, we demonstrate that a subset of SHREKs also blocks the infectivity of a hybrid alphavirus-SARS-CoV-2 (Ha-CoV-2) pseudovirus. These results suggest that SHREK proteins may be a part of host innate immunity against enveloped viruses.
Highlights
Mucins and mucin-like molecules are highly glycosylated, high-molecular-weight cell surface proteins that possess a semi-rigid and highly extended extracellular domain [1].P-selectin glycoprotein ligand-1 (PSGL-1), a mucin-like glycoprotein [2,3,4] has recently been found to restrict HIV-1 infectivity [5] through steric hindrance [6,7]
The extracellular domain of PSGL-1 consists of 14–16 decameric repeats (DR) with multiple O-glycosylated threonines
We found that when the DR domain was deleted from the N-terminus, the anti-HIV activity of PSGL-1 was abolished (Figure 1A,C) [6]
Summary
P-selectin glycoprotein ligand-1 (PSGL-1), a mucin-like glycoprotein [2,3,4] has recently been found to restrict HIV-1 infectivity [5] through steric hindrance [6,7]. PSGL-1 was found to be incorporated into virion particles, which inhibits virion attachment to target cells [6,7]. PSGL-1 shares structural features with other mucins and mucin-like proteins. It has a heavily glycosylated, elongated extracellular domain that extends nearly nm from the plasma membrane [8,9,10,11] and sterically hinders virus attachment to target cells when incorporated into virions [6,7]
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