RIPK2

RIPK2 is an innate immune adaptor kinase that connects cytosolic NOD1/NOD2 bacterial sensing to inflammatory signal transduction^[1]. Mechanistically, NOD1 and NOD2 CARD domains initiate RIPK2-CARD oligomerization, and RIPK2 filament formation supports NOD2-dependent NF-κB signaling^[1][2]. This pathway also depends on XIAP-RIPK2 association, because XIAP supports RIPK2 ubiquitination, NF-κB/MAPK activation, and cytokine production downstream of NOD2^[3][4]. In disease models, pharmacologic RIPK2 inhibition reduced inflammation in acute peritonitis and spontaneous Crohn disease-like ileitis, supporting RIPK2 as a practical target for inflammatory bowel disease research^[6]. Compared with related RIP kinase isoforms, RIPK2 shows a distinct signaling requirement, because replacing the RIPK2 kinase domain with the RIPK4 kinase domain failed to restore NOD2 signaling in RIPK2-deficient macrophages^[5]. For experimental applications, RIPK2 inhibitors such as WEHI-345, GSK583, ponatinib, and ATP-pocket-binding compounds can suppress NOD-driven signaling, with later studies emphasizing blockade of RIPK2-XIAP interaction rather than simple catalytic inhibition^[4][7][8].