LIGHT is a member of tumor necrosis factor (TNF) superfamily, and its function is mediated through lymphotoxin-beta receptor (LT beta R), which is known to play important roles in inflammatory and immune responses through activation of NF-kappa B signaling pathways. However, molecular mechanism of LT beta R ligation-induced NF-kappa B signaling remains incompletely understood. In this report we demonstrate that a novel zinc-finger protein 91 (ZFP91) is a critical regulator in LIGHT-induced activation of non-canonical NF-kappa B pathway. ZFP91 appears to be required for NF-kappa B2 (p100) processing to p52, nuclear translocation of p52 and RelB, and DNA-binding activity of NF-kappa B in LIGHT-induced activation of non-canonical NF-kappa B pathway. Furthermore, ZFP91 knock-down by RNA interference blocks the LIGHT-induced accumulation of NIK and p100 processing, as well as the expression of non-canonical NF-kappa B target genes. These data clearly indicate that ZFP91 is a key regulator in LIGHT-induced activation of non-canonical NF-kappa B pathway in LT beta R signaling. (C) 2010 Elsevier Inc. All rights reserved.