Biological and Medicinal Chemistry

Tensin Phosphatase-Like System of Hantavirus Facilitates Membrane Fusion to Disrupt Vascular permeability

Authors

Abstract

Increased vascular permeability is a characteristic of Hantavirus illness, for which there is now no treatment. We employed the domain search method to investigate the Hantavirus protein in this present work. The results indicated that the membrane glycoprotein E protein (containing Gn-Gc) of Hantavirus had lipid phosphatase and C2-like domains. The E protein was a tensin phosphatase-like (PTEN) enzyme that could shuttle in the cytoplasm and cell membrane. In an acidic endosomal environment, Gn dissociates, exposing Gc's autophosphorylation region to complete autophosphorylation and activating the C2 domain. The C2 domain facilitates Gc's conformational transition, which is followed by Gc binding to the endosomal membrane. After being inserted into the endosomal membrane, the phosphatase domain of Gc phosphorylates PI(3,4,5)P3 on the endosomal membrane. Then converted PI(3,4,5)P3 to PI(4,5)P2 . PI(4,5)P2 bound to the N-terminal of Gc, completely anchoring the tetramer-shaped Gc to the endosomal membrane and forming a fusion hole. Then analogous to PTEN, phosphorylation of PI(3,4,5)P3 directly induced the disintegration of Gc tetramer. The enlargement of the fusion pore speeded up the fusion of the viral and endosomal membranes. Through the fusion hole, the virus's intracellular material was swiftly discharged into the cytoplasm. The C2 domain promoted the PKC signaling route during Hantavirus membrane fusion, whereas the phosphatase inhibited the PI3K signaling pathway. E protein's PTEN-like action impaired lipid metabolism and endothelial cell remodeling, increasing blood vessel permeability and resulting in renal and cardiac syndromes. Additionally, E protein inhibited the immune system and Akt-mediated eNOS activation, resulting in a cascade of consequences.

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