GBP5 Promotes NLRP3 Inflammasome Assembly and Immunity in Mammals

TLDR

Inflammasomes are sensory complexes that detect infection or tissue damage by assembling NLR or ALR proteins to activate caspase‑1 and IL‑1β/IL‑18 secretion. The study identified the human protein guanylate binding protein 5 (GBP5) as a non‑NLR/ALR factor that stimulates inflammasome assembly. GBP5 selectively enhances NLRP3 inflammasome responses to pathogenic bacteria and soluble priming agents, and Gbp5‑deficient mice exhibit impaired caspase‑1/IL‑1β/IL‑18 cleavage and host defense, demonstrating that GBP5 acts as a unique rheostat for NLRP3 activation.

Abstract

Inflammasomes are sensory complexes that alert the immune system to the presence of infection or tissue damage. These complexes assemble NLR (nucleotide binding and oligomerization, leucine-rich repeat) or ALR (absent in melanoma 2-like receptor) proteins to activate caspase-1 cleavage and interleukin (IL)-1β/IL-18 secretion. Here, we identified a non-NLR/ALR human protein that stimulates inflammasome assembly: guanylate binding protein 5 (GBP5). GBP5 promoted selective NLRP3 inflammasome responses to pathogenic bacteria and soluble but not crystalline inflammasome priming agents. Generation of Gbp5(-/-) mice revealed pronounced caspase-1 and IL-1β/IL-18 cleavage defects in vitro and impaired host defense and Nlrp3-dependent inflammatory responses in vivo. Thus, GBP5 serves as a unique rheostat for NLRP3 inflammasome activation and extends our understanding of the inflammasome complex beyond its core machinery.