Regulation of GBP-mediated host defense

Regulation of GBP-mediated host defense Guanylate-binding protein 1 (GBP1) activity is tightly regulated to balance antimicrobial defense and prevent excessive inflammation. Caspase-1 (CASP1) cleaves GBP1 at aspartate 192 (D192), producing inactive fragments that lose the ability to target intracellular Salmonella Typhimurium, recruit caspase-4 (CASP4), or induce pyroptosis. This cleavage acts as a feedback mechanism to limit pyroptotic cell death during bacterial infection but does not occur during Toxoplasma gondii infection, indicating pathogen-specific regulation (Naschberger E et al., 2017; Fisch D et al., 2020). The kinase PIM1 phosphorylates GBP1 at Ser156 and Thr590, with Ser156 phosphorylation promoting binding to 14-3-3σ (SFN), which sequesters GBP1 in the cytosol and suppresses its membrane-associated antimicrobial activity (Fisch D et al., 2023). GTP binding disrupts the PIM1:GBP1 complex through an allosteric mechanism, highlighting how GBP1 integrates nucleotide- and phosphorylation-dependent control to fine-tune host defense (Persico M et al., 2015; De Donato M et al., 2012; Andreoli M et al., 2014).