FBXO36

FBXO36 (F-box only protein 36) is a small (188 aa) F-box protein that serves as a substrate-recognition component of an SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex (a Cullin-RING ligase 1, CRL1). It contains a single F-box domain (residues 91-137) through which it docks onto the adaptor SKP1, which in turn bridges to the scaffold CUL1; the catalytic RING subunit RBX1 recruits the ubiquitin-charged E2 enzyme. Within such complexes, the F-box protein contributes substrate selectivity rather than catalytic activity, directing assembly of polyubiquitin chains on bound substrates to target them for proteasomal degradation. FBXO36 belongs to the "FBXO" (F-box only, lacking recognizable C-terminal substrate-binding domains such as WD40 or LRR) class and remains very poorly characterized: no endogenous substrate, catalytic context, or subcellular localization has been experimentally validated. The strongest direct functional data come from a high-content siRNA screen of ubiquitin-pathway regulators of TNF signaling, in which FBXO36 depletion increased TNF-induced nuclear NF-kappa-B accumulation, prolonged late-stage I-kappa-B and JNK phosphorylation, sensitized cells to TNF+cycloheximide apoptosis, and raised steady-state beta-catenin levels; these phenotypes were interpreted as FBXO36 being a candidate modifier of SCF-dependent (e.g. SCF-betaTrCP) ubiquitin signaling, although no direct FBXO36 substrate was established. FBXO36 has also been noted among F-box genes with testis-enriched expression and appears in lower-confidence human genetic associations (a rare-variant lipoprotein-trait signal, lung-adenocarcinoma prognosis) that require replication. It is broadly but lowly expressed and has two annotated splice isoforms.