Host antiviral factors hijack furin to block SARS-CoV-2, ebola virus, and HIV-1 glycoproteins cleavage

Abstract

Viral envelope glycoproteins are crucial for viral infections. In the process of enveloped viruses budding and release from the producer cells, viral envelope glycoproteins are presented on the viral membrane surface as spikes, promoting the virus's next-round infection of target cells. However, the host cells evolve counteracting mechanisms in the long-term virus-host co-evolutionary processes. For instance, the host cell antiviral factors could potently suppress viral replication by targeting their envelope glycoproteins through multiple channels, including their intracellular synthesis, glycosylation modification, assembly into virions, and binding to target cell receptors. Recently, a group of studies discovered that some host antiviral proteins specifically recognized host proprotein convertase (PC) furin and blocked its cleavage of viral envelope glycoproteins, thus impairing viral infectivity. Here, in this review, we briefly summarize several such host antiviral factors and analyze their roles in reducing furin cleavage of viral envelope glycoproteins, aiming at providing insights for future antiviral studies.

Keywords: Antiviral factors; SARS-CoV-2; cleavage; furin; viral glycoprotein.

Figure 1.

The structure analysis of furin, GBP, MARCH8, α-SNAP, and PAR1 proteins. Each specific protein domain was indicated. In furin, SP, signal peptide; PP, proprotein; CD, catalytic domain; P, P domain; Cys, cysteine-rich domain; TM, transmembrane domain; Tail, cytoplasmic tail. In GBP, LG, large GTPase domain; HR, hinge region; MD, the middle domain; GED, GTPase effector domain. In MARCH8, RING, the E3 ubiquitin ligase activity domain; TM, transmembrane domain; Tail, cytoplasmic tail. In α-SNAP, Syn-binding, syntaxin-binding region; Syn/NSF-binding, syntaxin/NSF-binding region. In PAR1, N, N-terminus region; TM, transmembrane region; ICL1/2/3, intracellular loop 1/2/3/; ECL1/2/3, extracellular loop 1/2/3.

Figure 2.

A. The model of GBP2/5 inhibiting furin cleavage of HIV-1 envelope (Env) glycoprotein. HIV-1 Env is high-mannose N-glycosylated in ER and then transported to the Golgi network. At TGN, HIV-1 Env (gp160) completes complex N-glycosylation modification and is processed by furin into gp120 and gp41 subunits, which are then relinked formed homologous self-trimer. The trimeric gp120-gp41 glycoproteins are subsequently transported to the plasma membrane. GBP2/5 could recognize and bind to furin at TGN and thus suppresses furin cleavage of HIV-1 gp160. The uncleaved gp160 trimer could be transported to the plasma membrane but makes the nascent virion particles less active than those containing the cleaved gp120-gp41 trimer after being integrated into the viral membranes. B. Furin domain recognized by GBP2/5.

Figure 3.

A. The model of MARCH8 suppresses the cleavage and glycosylation maturation of EBOV GP. In ER, EBOV GP starts high-mannose N-glycosylation. After entry into the Golgi network, EBOV GP experiences complex N-glycosylation and O- glycosylation and is cleaved into two GP subunits (GP1 and GP2) by host furin proprotein convertase. The GP1 and GP2 relink and form the self-trimer, which is then transported to the cell surface. However, at TGN, in the presence of MARCH8, furin cleavage activity is blocked. Correspondingly, EBOV GP is unable to be cleaved by furin. In addition, MARCH8 traps the EBOV GP at TGN, leading to its retention and thus blocking its further transportation to the cell plasma membrane. PM: plasma membrane; TGN: trans-Golgi network; ER: endoplasmic reticulum. B. Furin domain recognized by MARCH8.

Figure 4.

A. The model of α-SNAP suppressing the cleavage of SARS-CoV-2 Sipke (S) glycoprotein. SARS-CoV-2 S glycoprotein is synthesized, high-mannose N-glycosylated, and trimerized in ER, where it is transported to the Golgi network. The S trimer is modified with complex N-glycosylation and O- glycosylation, cleaving into S1 and S2 subunits by furin. The S1-S2 trimer is transported to the ER-Golgi intermediate compartment (ERGIC) through retrograde trafficking or lysosome, where the virus assembly and egress happen. The S glycoprotein cleavage is blocked in the presence of α-SNAP at TGN. When integrated into the SARS-CoV-2 virion particles, the virion with uncleaved S glycoprotein is less infectious than that with cleaved S1-S2 glycoprotein. B. Furin domain recognized by α-SNAP. EC, extracellular space.

Figure 5.

A. The model of PAR1 suppressing the cleavage of HIV-1 glycoprotein. As described in Figure 2, HIV-1 gp160 needs to be cleaved by furin. PAR1 interacts with furin, which is downregulated by PACS-1 from the plasma membrane and trapped at TGN, where furin is inhibited from cleaving HIV-1 gp160. B. Furin domain recognized by PAR1.