Absence of GdX/UBL4A protects against inflammatory bowel diseases by regulating NF-{kappa}B signaling in DCs and macrophages

Nuclear factor-kappa B (NF-κB) activation is critical for innate immune responses. Here we report that the UBL4A (Ubiquitin-like protein 4A, also named GdX) enhances dendritic cells (DCs) and macrophages (Mϕ)-mediated innate immune defenses by positively regulating NF-κB signaling. GdX-deficient mice were resistant to LPS-induced endotoxin shock and DSS-induced colitis. DC- or Mϕ- specific GdX-deficient mice displayed alleviated mucosal inflammation, and the production of pro-inflammatory cytokines by GdX-deficient DCs and Mϕ was reduced. Mechanistically, we found that PTPN2 (TC45) and PP2A form a complex with RelA (p65) to mediate its dephosphorylation whereas GdX interrupts the TC45/PP2A/p65 complex formation and restrict p65 dephosphorylation by trapping TC45. Our study provides a mechanism by which NF-κB signaling is positively regulated by an adaptor protein GdX in DC or Mϕ to maintain the innate immune response. Targeting GdX could be a strategy to reduce over-activated immune response in inflammatory diseases.