Ubiquitin in NFKB Signaling

Binding of TNFα to its receptor induces the recruitment of signaling proteins, including the adaptor TRADD, ubiquitin ligases TRAF2, TRAF5, cIAP1 and cIAP2, and protein kinase RIP1. RIP1 and TRAFs are polyubiquitinated by TRAFs and/or cIAPs, and the polyubiquitin chains recruit and activate the TAK1 and IKK complexes, leading to activation of NF-κB and MAP kinases (e.g, JNK). To shut down the signaling cascades, the deubiquitination enzymes A20 and CYLD remove the polyubiquitin chains from RIP1 and TRAFs. In addition, A20 forms a ubiquitin-editing complex with the ubiquitin-binding protein TAX1BP1 and the HECT domain ubiquitin ligase ITCH. This complex targets RIP1 for K48 polyubiquitination and proteasomal degradation. Ubiquitination and deubiquitination also regulate the RIG-I pathway, which detect viral infection in the cytosol. Binding of RIG-I to viral RNA triggers its K63 polyubiquitination by the RING domain E3 TRIM25. RIG-I then interacts with the mitochondrial adaptor protein MAVS, which recruits TRAF6 and TRAF3 to activate IKK and TBK1, respectively. TBK1 phosphorylates IRF3, leading to induction of type-I interferons. CYLD and DUBA are deubiquitination enzymes that remove K63 polyubiquitin chains from RIG-I and TRAF3, respectively, thereby damping the antiviral response.

Publication

Ubiquitin in NF-κB Signaling. () Yu-Hsin Chiu, et al. Chem Rev. ;109(4):1549-1560. Figure: F3. All organisms Homo sapiens Mus musculus Cervus elaphus Drosophila melanogaster Danio rerio

Disease mentions