Mechanisms and functions of guanylate-binding proteins and related interferon-inducible GTPases: Roles in intracellular lysis of pathogens

Abstract

Guanylate-binding proteins (GBPs) are a group interferon-inducible GTPases within the constellation of the dynamin GTPase superfamily. These proteins restrict the replication of intracellular pathogens in both immune and non-immune cells. GBPs and their related family members immunity-related GTPases target and lyse the membrane of the pathogen-containing vacuole, destroying the residential niche of vacuolar protozoal and bacterial pathogens. They also prevent virion infectivity and target replication complexes of ribonucleic acid viruses. The exciting concept that GBPs and immunity-related GTPases can directly target the membrane of bacteria and protozoa has emerged. Rupture and lysis of the pathogen membrane mediates liberation of concealed microbial ligands for activation of innate immune sensing pathways and the inflammasome. Further studies have demonstrated a capacity of GBPs to recruit additional antimicrobial factors, highlighting the complexity of the molecular mechanisms involved in pathogen killing. In this mini-review, we discuss recent advances describing the localisation and functions of GBPs on the host and pathogen membrane. We also highlight unresolved questions related to the regulation of GBPs in cell-autonomous immunity to intracellular pathogens.

Safe haven under constant attack-TheChlamydia-containing vacuole

“…Such an alternative explanation for LC3-activation was postulated by Al-Younes and colleagues who showed that Ctr interact via LC3 and MAP 1 with the microtubule network to obtain access to metabolite-rich vesicles. In line with these findings, inactivation of autophagy (Meunier & Broz, 2016;Ngo & Man, 2017). On the other hand, GBPs also target pathogen-containing vacuoles but function by recruiting antimicrobial protein complexes that produce reactive oxygen species or components of the autophagy machinery .…”

“…Therefore, each Chlamydia strain established individual mechanisms to counteract IFN‐mediated defence of the respective host cell (McClarty, Caldwell, & Nelson, ; Nelson et al, ; Roshick, Wood, Caldwell, & McClarty, ). IFNγ stimulation induces the expression of hundreds of IFN‐stimulated genes, among them members of the IFN‐inducible GTPase families IRGs (immunity‐related GTPase) and guanylate‐binding proteins (GBPs; Haldar et al, ; Pilla‐Moffett, Barber, Taylor, & Coers, ; Ngo & Man, ). IRGs target pathogen‐containing vacuoles to induce membrane destabilisation, vacuole rupture, and clearance by autophagy (Meunier & Broz, ; Ngo & Man, ).…”

“…IFNγ stimulation induces the expression of hundreds of IFN‐stimulated genes, among them members of the IFN‐inducible GTPase families IRGs (immunity‐related GTPase) and guanylate‐binding proteins (GBPs; Haldar et al, ; Pilla‐Moffett, Barber, Taylor, & Coers, ; Ngo & Man, ). IRGs target pathogen‐containing vacuoles to induce membrane destabilisation, vacuole rupture, and clearance by autophagy (Meunier & Broz, ; Ngo & Man, ). On the other hand, GBPs also target pathogen‐containing vacuoles but function by recruiting antimicrobial protein complexes that produce reactive oxygen species or components of the autophagy machinery (Kim et al, ).…”

Guanylate-binding proteins at the crossroad of noncanonical inflammasome activation during bacterial infections

“…Genes encoding murine GBPs, mGBP1, mGBP2, mGBP3, mGBP5, and mGBP7 are clustered on chromosome 3 (GBP chr3 ), whereas genes encoding mGBP4, mGBP6, mGBP8, mGBP9, mGBP10, and mGBP11 are located on chromosome 5 . GBPs are primarily found in the cytoplasm, associated with intracellular membranes, within vesicle‐like structures or in the nucleus, and exhibit antimicrobial effects against intracellular bacteria, viruses, and protozoa …”

“…45,[48][49][50] GBPs are primarily found in the cytoplasm, associated with intracellular membranes, within vesicle-like structures or in the nucleus, [50][51][52][53] and exhibit antimicrobial effects against intracellular bacteria, viruses, and protozoa. 45,54,55 GBPs-dependent effects on noncanonical inflammasome activation have been shown in several vacuolar and cytosolic bacterial pathogens, including S. typhimurium, Legionella pneumophila, V. cholerae, S. flexneri, C. rodentium, Chlamydia trachomatis, Chlamydia muridarum, and type 3 secretion system (T3SS)-negative Pseudomonas aeruginosa. 26,42,44,56,57 For instance, mice M s deficient in GBP chr3 showed reduced levels of noncanonical inflammasome activation and pyroptosis during infection with S. typhimurium and L. pneumophila.…”