FBXO15

FBXO15 (F-box only protein 15, FBX15) is a 510-amino-acid F-box protein of the "FBXO/other" class that serves as the substrate-recognition component of an SCF (SKP1-CUL1-F-box protein, also called CRL1) cullin-RING E3 ubiquitin ligase complex. Like other F-box proteins, it docks onto the SCF core through its F-box domain (residues 77-117), which binds the adaptor SKP1; SKP1 in turn bridges to the scaffold CUL1 and the catalytic RING subunit RBX1 that recruits the ubiquitin-charged E2 enzyme. FBXO15 therefore does not itself possess catalytic ubiquitin-transfer activity; it confers substrate specificity on the ligase, positioning a bound target protein for poly-ubiquitination and subsequent proteasomal degradation. Several substrates have been experimentally reported, often recruited through modification-dependent degrons: FBXO15 uniquely associates with and degrades cardiolipin synthase 1 (CLS1) in a PINK1-linked module (phospho-Thr219-dependent recognition; CLS1 Lys174 ubiquitination), an ER/cytosol-associated activity that limits mitochondrial cardiolipin and has been implicated in pneumonia/lung-injury models; it cooperates with the E2 CDC34/UBE2R1 to ubiquitinate the drug-efflux transporter P-glycoprotein (ABCB1/MDR1), so that FBXO15 loss raises P-gp levels and multidrug resistance; and in breast cancer it promotes ubiquitin-dependent degradation of the stemness/signaling factors SOX2 and STAT3, dampening EGFR/ERK/STAT3 signaling and acting as a tumor suppressor (higher FBXO15 expression correlating with better survival). In mouse embryonic stem cells the ortholog recognizes an acetyldegron on KBP (acetyl-Lys501) and is preferentially expressed in undifferentiated cells, linking it to pluripotency biology. FBXO15 is expressed broadly with enhancement in testis and fallopian tube. Two splice isoforms are produced, the shorter of which lacks the N-terminal region preceding the F-box domain. Despite these reports, most substrate-pathway links rest on individual studies and the integrated physiological role of human FBXO15 remains only partly defined.