The HRAS-binding C2 domain of PLCη2 suppresses tumor‐like synoviocytes and experimental arthritis in rheumatoid arthritis

Fibroblast-like synoviocytes (FLSs), which are stromal cells that play key roles in rheumatoid arthritis (RA) pathophysiology, are characterized by a tumor-like phenotype and immunostimulatory actions. C2 domains in various proteins play roles in intracellular signaling and altering cellular characteristics, and some C2 domain-containing proteins exacerbate or alleviate certain malignant or inflammatory diseases. However, the roles of C2 domains in regulating the functions of RA FLSs remain unclear. Here we performed functional C2 domainomics with 144 C2 domain-containing viral vectors and identified the C2 domain of PLCη2 as a key regulator of RA FLSs. In mice, overexpressing PLCη2 or only its C2 domain PLCη2 (PLCη2_C2) diminished the proliferation, migration, invasion and inflammatory responses of RA FLSs, mitigating RA pathology; the absence of PLCη2 amplified these proinflammatory and destructive processes in RA FLSs in vivo. Mechanistically, PLCη2 and PLCη2_C2 participate in the pathological signaling of RA FLSs in a calcium-independent manner through protein–protein interactions. Specifically, PLCη2_C2 disrupted HRAS–RAF1 interactions, suppressing downstream signaling pathways, including the NF-κB, JAK–STAT and MAPK pathways. Collectively, these findings establish PLCη2 and PLCη2_C2 as novel inhibitory regulators in RA, suggesting promising therapeutic avenues for addressing FLS-driven disease mechanisms.