GBP-mediated host defense

GBP-mediated host defense The human Guanylate Binding Proteins (GBPs) constitute a family of dynamin-related GTPase, comprising seven members, GBP1 to GBP7 (Kutsch M & Coers J 2021). GBPs are primarily induced by type II interferon-gamma (IFN-γ) and function as key effectors in cell-autonomous immunity against a wide range of intracellular pathogens, many of which reside in pathogen-containing vacuoles. For example, GBPs protect against intracellular bacterial pathogens such as Listeria monocytogenes, Shigella flexneri, Mycobacterium tuberculosis, and Salmonella enterica serovar Typhimurium, as well as protozoan parasites including Toxoplasma gondii (Fisch D et al., 2019; Santos JC et al., 2020). Upon infection, GBPs are recruited to the surface of pathogen‑containing vacuoles or directly to LPS-rich bacterial membrane surfaces, where they oligomerize into a dense protein coat (Pandita E et al., 2016; Zhu S et al., 2024; Kuhm T et al., 2025). Their assembly can disrupt or remodel membranes or promote caspase 4 (CASP4)-mediated inflammatory cell death.GBPs consists of an N-terminal large GTPase domain (LG) and an elongated helical domain, which can be further divided into a middle domain and a C-terminal GTPase effector domain (GED) (Prakash B et al., 2000). The biochemically best-characterized member is GBP1. Its C-terminal CAAX motif undergoes farnesylation catalyzed by the farnesyltransferase (FNT) complex (Nantais CA et al., 1996; Shydlovskyi S et al., 2017; Sistemich L et al., 2020).GBP1-catalyzed GTP hydrolysis to GMP proceeds in two sequential steps (GTP→GDP→GMP) within the LG domain. GTP binding induces GBP1 dimerization in the cytosol, which promotes hydrolysis of GTP to GDP (Ghosh A et al., 2006; Ince S et al., 2021). Subsequent membrane recruitment is associated with a large-scale rearrangement of the middle domain relative to the LG domain via a hinge region. In addition, the C-terminal GED is released from the middle domain, allowing the farnesyl anchor to insert into the membrane (Weismehl M et al., 2024; Zhu S et al., 2024; Kuhm T et al., 2025). These conformational changes drive GBP1 oligomerization, a prerequisite for its antimicrobial activity ((Ghosh A et al., 2006; Schwemmle M & Staeheli P, 1994; Ince S et al., 2021; Weismehl M et al., 2024). In a subsequent step, the nucleotide is repositioned within the catalytic pocket so that the same catalytic residues promote further hydrolysis of GDP to GMP (Ghosh A et al., 2006; Ince S et al., 2021). In the GMP-bound form, the GBP1 coat is thought to disassemble. The reaction product, GMP, can be further metabolized to uric acid, a potential trigger of NLRP3 inflammasome under certain cellular conditions (Xavier A et al., 2020).Once membrane-bound, GBP1 recruits additional GBP members, namely GBP2, GBP3 and GBP4, to form antimicrobial oligomeric complexes (Santos JC et al., 2020; Valeva SV et al., 2023). GBP2, which is geranylgeranylated at C588 within its CAAX motif, cooperates with GBP1 in localizing to bacterial membranes and assembling GBPs antimicrobial coats (Britzen-Laurent N et al., 2010; Dickinson MS et al., 2023). This multimeric GBP coat compromises microbial membrane integrity (Sistemich et al., 2020, 2021; Kutsch M et al., 2020) and/or facilitates activation of caspase-4 (CASP4), promoting non-canonical inflammasome assembly. Activation of CASP4 leads to pyroptotic cell death and maturation and secretion of inflammatory cytokines interleukin-18 (IL-18) and IL-1β (Santos JC et al., 2020; Wandel MP et al., 2020; Zhu S et al., 2024). GBP1 also inhibits actin-based motility of Shigella flexneri by coating the bacterial surface, thereby blocking IcsA-mediated recruitment of N-WASP and subsequent actin polymerization (Kutsch M et al., 2021). S. flexneri counters this restriction by secreting the E3 ligase IpaH9.8, which ubiquitinates and degrades GBPs (Piro AS et al., 2017). GBP1 activity is regulated by PIM1-mediated phosphorylation at S156, promoting its interaction with 14-3-3σ (SFN), which sequesters GBP1 in the cytosol and prevents membrane association (Fisch D et al., 2023). GTP binding allosterically disrupts this inhibitory interaction (Persico M et al., 2015), allowing GBP1 to resume antimicrobial function.In addition to their antibacterial activities, GBPs mediate antiviral responses, for example against herpesviruses, flaviviruses, and retroviruses. In particular, GBP1 restricts the nuclear delivery of DNA viruses such as Kaposi’s sarcoma associated herpesvirus (KSHV) (Zou Z et al., 2017). This may occur through binding and sequestering monomeric G-actin, thereby reducing the pool of polymerization-competent actin, remodeling the actin cytoskeleton, and disrupting actin-dependent intracellular trafficking (Ostler N et al., 2014). In addition, GBP2 and GBP5 inhibit the infectivity of a broad range of enveloped RNA viruses, including human immunodeficiency virus type 1 (HIV-1), Zika virus, measles virus, influenza A virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Braun E et al., 2019; Mesner D et al., 2023). Both proteins interact with the host proprotein convertase furin (PCSK3), binding to its C-terminal cytoplasmic tail and inhibiting the proteolytic cleavage of viral envelope glycoproteins, such as the HIV-1 envelope glycoprotein gp160 and the SARS-CoV-2 spike glycoprotein (Braun E et al., 2019; Cui W et al., 2021). This inhibition disrupts glycoprotein maturation, intracellular trafficking, and incorporation into nascent virions, thereby reducing viral infectivity (Braun E et al., 2019; Cui W et al., 2021; Mesner D et al., 2023). GBP2 and GBP5 may also restrict viral infectivity by altering trafficking and N-linked glycosylation of viral glycoproteins independently of furin (Krapp C et al., 2016; Cui W et al., 2021; Veler H et al., 2024; reviewed by Sauter D & Kirchhoff F 2024).