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FBXO21 is an SCF (SKP1-CUL1-RBX1) substrate receptor with validated substrates EID1, ASK1, p85alpha/PIK3R1, and ABCB1/P-gp, operating in both proteolytic and non-proteolytic ubiquitination modes.
"The research target is **human FBXO21** (UniProt **O94952**; gene **FBXO21**, synonyms **FBX21**, **KIAA0875**), an **F-box only** protein that functions as a substrate-recognition subunit of an **SCF (SKP1–CUL1–RBX1) Cullin-RING E3 ubiquitin ligase** complex. This identity is consistent across primary literature describing **SCF^FBXO21** and its validated substrates (EID1, ASK1, p85α/PIK3R1, and ABCB1/P-gp)."
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SCF(FBXO21) mediates non-proteolytic Lys29-linked ubiquitination of ASK1 (MAP3K5) that promotes ASK1 activation rather than degradation, driving antiviral innate signaling and type I interferon responses.
"SCF^FBXO21 mediates **Lys29-linked ubiquitination** of ASK1, demonstrated using ubiquitin mutants (K29-only ubiquitin), and this modification is **non-proteolytic** (ASK1 degradation not affected)."
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FBXO21 deficiency impairs virus-induced ASK1-JNK/p38 and IRF3 signaling and reduces IL-6 and IFN-beta induction after viral or nucleic-acid challenge.
"FBXO21 deficiency impaired virus-induced signaling (reduced JNK/p38 and IRF3 activation; reduced nuclear c-Fos/IRF3) and reduced **IL-6 and IFNβ** induction after LPS, nucleic acid agonists, and VSV/HSV-1 infection, linking FBXO21→ASK1 ubiquitination to **ASK1–JNK/p38** antiviral signaling and type I interferon responses."
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In acute myeloid leukemia, FBXO21 ubiquitinates the PI3K regulatory subunit p85alpha (PIK3R1) for proteasomal degradation, shaping PI3K/AKT versus ERK signaling; silencing FBXO21 promotes differentiation and chemosensitization.
"Stabilization of p85α (via FBXO21 knockdown) is associated with reduced canonical PI3K signaling (decreased AKT activation) and increased ERK activation in the model, with p85α homodimerization proposed as a mechanistic intermediate; the paper’s model schematic is captured in retrieved figures."
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FBXO21 binds and ubiquitinates the multidrug-resistance transporter ABCB1/P-glycoprotein for proteasomal degradation, a turnover that Ser291-phosphorylated CD44 suppresses.
"CD44 physically associates with P-gp at the membrane, and a **Ser291-phosphorylated** form of CD44 inhibits FBXO21-directed degradation of P-gp (Ser291Ala loses protection)."