FBXO22

FBXO22 (F-box only protein 22, FBX22p44) is a 403-residue F-box protein that serves as the substrate-recognition receptor of a SCF (SKP1-CUL1-F-box)-type CUL1-RING E3 ubiquitin ligase complex. It binds the SCF core through an N-terminal F-box motif (residues ~21-67) that docks onto SKP1, while a C-terminal FIST-C/substrate-binding region engages target proteins; in the assembled SCF, the catalytic RING subunit RBX1 recruits the ubiquitin-charged E2, so FBXO22 itself contributes substrate selection rather than catalysis. Through this adaptor role FBXO22 directs polyubiquitination and proteasomal degradation of a defined set of substrates and thereby influences chromatin/transcriptional regulation, the DNA-damage and senescence response, oxidative-stress signaling, nutrient sensing, immune-checkpoint control, and antiviral defense. Documented substrates include the histone demethylases KDM4A/JMJD2A (controlling H3K9 and H3K36 methylation) and KDM4B (when KDM4B is complexed with tamoxifen-bound estrogen receptor, governing selective-estrogen-receptor- modulator pharmacology in breast cancer), methylated TP53 (in complex with KDM4A, at late senescence), the transcription factor BACH1 (upon oxidative-stress-induced exposure of its degron), nuclear (but not cytoplasmic) PTEN (ubiquitinated at Lys221), the immune-checkpoint ligand PD-L1 (CD274; degradation sensitizes cells to DNA-damaging therapy), the co-chaperone BAG3 (via an ERK-dependent phosphodegron, S377), the kinase MTOR (both K27-linked ubiquitination at Lys2066 upon amino-acid depletion to inhibit mTORC1, and degradation of the Ser2448-phosphorylated form), the transcription factor KLF4, and sarcomeric proteins; it also degrades the SARS-CoV-2 3C-like proteinase NSP5 via K48-linked chains to restrict viral replication. Many of these recognition events are post-translational-mark dependent (methylation marks, or phosphodegrons such as ERK-phosphorylated S377 of BAG3), consistent with a C-terminal substrate-binding region that reads modified degrons. A surface cysteine (Cys326) in the C-terminal domain can be covalently engaged by small molecules, making FBXO22 a recruitable E3 for targeted protein degradation. FBXO22 is broadly expressed with enrichment in liver and cardiac muscle and localizes to both the cytoplasm and nucleus, with its subcellular distribution modulated by EIF2AK4/GCN2-dependent phosphorylation at Thr-127. Biallelic loss-of-function causes Tayoun-Maawali syndrome (TYMAS), an autosomal-recessive multisystem developmental disorder.