Identification of the SHREK Family of Proteins as Broad-Spectrum Host Antiviral Factors

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.

SERPINE1 rs6092 Variant Is Related to Plasma Coagulation Proteins in Patients with Severe COVID-19 from a Tertiary Care Hospital

“…The increase of D-dimer levels has been mainly correlated with COVID-19 severity and inhospital mortality [37]. PSGL-1 was not previously determined in patients with COVID-19, but it has been reported that this glycoprotein is incorporated into virion particles, inhibiting the virion attachment to target cells [38,39]. Moreover, this glycoprotein has been described as a critical regulatory molecule in the activation of platelets, leukocytes, and vascular endothelial cells; and the expression of tissue factors on leukocytes, the serum levels of inflammatory factors, fibrinogen deposition, as well as other immunologic and coagulation disturbances, are alleviated when the glycoprotein is blockaded with a PSGL-1 antibody in endotoxemic mice [40].…”

Influenza Virus Host Restriction Factors: The ISGs and Non-ISGs

“…MUC1 (mucin 1) is a member of mucins, a family of highly glycosylated proteins that are expressed on the surface of respiratory epithelial cells, which are the target of influenza virus infection. MUC1 potentially acts as a receptor decoy and inhibits influenza virus infection by binding to virus particles and blocking their attachment to target cells [ 201 , 202 , 203 ].…”

Roles of Virion-Incorporated CD162 (PSGL-1), CD43, and CD44 in HIV-1 Infection of T Cells

“…Furthermore, cryo-electron tomography revealed that the extended pre-hairpin intermediate of Env observed between a target cell membrane and cell-attached HIV-1 in the presence of fusion inhibitors is 15.6 ± 2.8 nm [108], i.e.,~3 fold shorter than the lengths of the extracellular domains of PSGL-1 and CD43. More recently, it has been reported that mucins and mucin-like proteins, which include not only PSGL-1 and CD43 but also CD164, PODXL1, PODXL2, CD34, TMEM123, and MUC1, that have elongated extracellular domains inhibit HIV-1 attachment to target cells when these proteins are overexpressed in virus-producing cells [109]. Since these proteins abolish HIV-1 infectivity and share structural features, these proteins were named the surface-hinged, rigidly-extended killer (SHREK) family of proteins.…”

“…This study provides additional support to the possible anti-viral mechanism by which PSGL-1 and CD43 sterically hinder HIV-1 attachment to target cells through their elongated extracellular domains. SHREK family proteins reduce the infectivity not only of HIV-1 but also of other enveloped viruses, such as influenza A virus (IAV) and severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 [26,109,110]. In addition, PSGL-1 reduces the infectivity of murine leukemia virus (MLV) [26].…”