Protective role for the N-terminal domain of α-dystroglycan in Influenza A virus proliferation

Abstract

α-Dystroglycan (α-DG) is a highly glycosylated basement membrane receptor that is cleaved by the proprotein convertase furin, which releases its N-terminal domain (α-DGN). Before cleavage, α-DGN interacts with the glycosyltransferase LARGE1 and initiates functional O-glycosylation of the mucin-like domain of α-DG. Notably, α-DGN has been detected in a wide variety of human bodily fluids, but the physiological significance of secreted α-DGN remains unknown. Here, we show that mice lacking α-DGN exhibit significantly higher viral titers in the lungs after Influenza A virus (IAV) infection (strain A/Puerto Rico/8/1934 H1N1), suggesting an inability to control virus load. Consistent with this, overexpression of α-DGN before infection or intranasal treatment with recombinant α-DGN prior and during infection, significantly reduced IAV titers in the lungs of wild-type mice. Hemagglutination inhibition assays using recombinant α-DGN showed in vitro neutralization of IAV. Collectively, our results support a protective role for α-DGN in IAV proliferation.

Structure of Furin Protease Binding to SARS-CoV-2 Spike Glycoprotein and Implications for Potential Targets and Virulence

“…Furin protease belongs to the family of calcium (Ca 2+ )-dependent proprotein/prohormone convertases (PCs) that are ubiquitously expressed in humans, and its levels are significantly elevated in lung cystic fibrosis. 15 Furin protease also cycles among the trans-Golgi network (TGN), the cell membrane (viral attachment), and endosomes (viral translocation in the endosomes). Furin recognizes the R-X-K/R-R motif and cleaves the peptide in the presence of Ca 2+ 16 , 17 and is also known for cleaving different viral (influenza and HIV) envelope glycoproteins, thereby enhancing fusion of the virus with the host cell membrane.…”

Virus strain from a mild COVID-19 patient in Hangzhou represents a new trend in SARS-CoV-2 evolution potentially related to Furin cleavage site

“…Strikingly, compared with RaTG13, we found an additional PRRA sequence at the F1 site of SARS-CoV-2 forming a strong and reliable FCS (Furin score 0.62). Although the source of insertion was unknown, the PRRA sequence was common to avian influenza virus [29]. We deduced that it might have been inherited from HKU1 and OC43, which had effective FCS at the F1 site (Furin score 0.878 and 0.744) and the respective amino acid sequence of SSRRKRR and TKRRSRR, with high similarity of NSPRRAR in SARS-CoV-2.…”

Virus strain of a mild COVID-19 patient in Hangzhou represents a new trend in SARS-CoV-2 evolution related to Furin cleavage site

“…Among ZJ01 unique mutations, 10 (NO. [22][23][24][25][26][27][28][29][30][31] were located on the S protein, including 3 samesense mutation, 2 deletion mutation and 5 missense mutation, which led to amino acid changes of Ser596, Gln613, Glu702, Ala771, Ala1015, Pro1053 and Thr1066. Further similarity analysis indicated that the main difference among various coronaviruses located in the Receptor Binding Domain (RBD) region of S1.…”

“…Strikingly, we found an additional PRRA sequence in the F1 site of SARS-CoV-2 when compared with RaTG13, forming a strong and reliable FCS (Furin score 0.62). Though the source of insertion was unknown, the PRRA sequence was common in Avian Influenza virus 29 . We deduced that its source might inherit from is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint HKU1 and OC43, which had effective FCS in F1 site (Furin score 0.878 and 0.744) and respective amino acid of SSRRKRR and TKRRSRR, with high similarity of NSPRRAR in SARS-CoV-2.…”