UC San Diego

Crohn’s disease is a prevalent inflammatory bowel disease characterized by chronic inflammation of the gastrointestinal tract due to a hyperactive immune system. The disease is predominantly caused by a mutation in the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene which detects a constituent of bacteria, muramyl dipeptide (MDP), and triggers protective inflammatory immune promoting bacterial clearance. However, the cellular mechanisms underlying how these mutations lead to chronic inflammation remain incompletely understood. Previous studies have shown that the guanine nucleotide-binding (G) protein ⍺-subunit (G⍺)-interacting vesicle-associated protein (GIV, also known as “Girdin”) is essential in modulating the innate immune sensors including Toll-like receptor 4 (TLR4) and NOD2. In this thesis, we aim to understand the cellular and molecular mechanisms underlying the interactions between GIV and NOD2 in macrophage, which are critical in bacteria sensing and clearance. Using biochemical and functional immunology studies, our research shows that GIV binds to NOD2 and is required for effective MDP/NOD2-mediated protective signaling and bacterial clearance. We further found that GIV and NOD2 mutually regulate each other’s functions for effective intracellular bacteria sensing by NOD2 and cAMP/PKA dependent phagolysosome maturation and bacterial clearance by GIV. In conclusion, this crosstalk is essential for gut immune homeostasis, provides valuable insight into the cellular mechanisms underlying Crohn’s disease, and can be exogenously manipulated for therapeutic purposes to enhance infection resolution and restore gut homeostasis.