When human guanylate-binding proteins meet viral infections

Abstract

Innate immunity is the first line of host defense against viral infection. After invading into the cells, pathogen-associated-molecular-patterns derived from viruses are recognized by pattern recognition receptors to activate the downstream signaling pathways to induce the production of type I interferons (IFN-I) and inflammatory cytokines, which play critical functions in the host antiviral innate immune responses. Guanylate-binding proteins (GBPs) are IFN-inducible antiviral effectors belonging to the guanosine triphosphatases family. In addition to exerting direct antiviral functions against certain viruses, a few GBPs also exhibit regulatory roles on the host antiviral innate immunity. However, our understanding of the underlying molecular mechanisms of GBPs' roles in viral infection and host antiviral innate immune signaling is still very limited. Therefore, here we present an updated overview of the functions of GBPs during viral infection and in antiviral innate immunity, and highlight discrepancies in reported findings and current challenges for future studies, which will advance our understanding of the functions of GBPs and provide a scientific and theoretical basis for the regulation of antiviral innate immunity.

Keywords: Antiviral roles; GBPs; IFN-I; Innate immunity; Virus.

Fig. 1

The direct antiviral functions of GBPs. a GBP1 suppresses the replication of EMCV, DENV, HSV-1, HCV, CSFV, PRRSV. GBP1 represses the genomic transcription of VSV by competitively binding to the VSV-N substituting for the VSV-P, inhibits the nuclear delivery of KSHV virions by disrupting the actin filaments, and inactivating the viral particle of HEV by targeting the viral capsid protein to the lysosomal compartment. b GBP2 inhibits the replication of VSV and EMCV, andorchestrates IFN-γ-mediated immune responses against MNV-1. GBP2 and GBP5 inhibit the replication of HIV, IAV, MLV, ZIKV, MeV, MARV and HERV-K by suppressing furin to reduce the diverse viral envelope glycoproteins. GBP5 prevents RSV replication by enhancing its SH protein release. c GBP3 inhibits the replication of the influenza virus by disrupting the viral polymerase complex to reduce viral RNA and protein synthesis. EMCV encephalomyocarditis virus, DENV dengue virus, HSV-1 herpes simplex virus type 1, HCV hepatitis C virus, CSFV classical swine fever virus, PRRSV porcine reproduction and respiratory syndrome virus, VSV vesicular stomatitis virus, VSV-N nucleoprotein, VSV-L large protein, VSV-P phosphoprotein, KSHV Kaposi's sarcoma-associated herpesvirus, HEV hepatitis E virus, MNV-1 murine norovirus-1, HIV human immunodeficiency virus-1, IAV influenza A virus, MLV murine leukemia virus, ZIKV Zika virus, Mev measles virus, MARV Marburg virus, HERV-K human endogenous retrovirus K, RSV respiratory syncytial virus, SH small hydrophobic

Fig. 2

GBPs regulate host antiviral innate immune signaling pathways. a GBP4 negatively regulates IFN-I by impairing TRAF6-mediated ubiquitination and transactivation of IRF7. GBP5 represses replication of IAV by interacting with the NF-κB-essential modulator complex to promote IFN and proinflammatory factors expression. b GBP7 impedes NF-κB translocation to the nucleus by preventing the phosphorylation of IκBα and inhibits the JAK–STAT signaling pathway by attenuating the phosphorylation of STAT1 and STAT2. P phosphate, Ub ubiquitin