Ubiquitin Signaling in the NFKB Pathway

Polyubiquitination by TRAF2 and TRAF6 not only mediates signaling by TNFR, IL1R and TLR (see ) in the innate immunity pathways, but also plays an important role in adaptive immune responses by activating IKK in response to stimulation of TCR. In T cells, BCL10 and MALT1 activate the ligase activity of TRAF6 (and possibly TRAF2), to catalyze the K63-linked polyubiquitination of NEMO and TRAF6 itself. These ubiquitination events mediate the activation of TAK1 and IKK. NOD2 and RIP2, which trigger innate immune responses against intracellular bacteria, also facilitate the K63-linked polyubiquitination of NEMO. DNA damage leads to the sumoylation and subsequent ubiquitination of NEMO in the nucleus. The ubiquitinated NEMO then exits the nucleus and associates with the other subunits of the cytosolic IKK complex, resulting in IKK activation. Some receptors of the TLR family, including TLR7, 8 and 9, are localized in the endosomal membrane. Stimulation of TLR7/8 and TLR9 by viral RNA and CpG DNA, respectively, leads to the activation of both NF-κB and IRF7, which coordinately regulate interferon production. IRF7 binds to MyD88, which is associated with the endosomal TLRs as well as IRAK and TRAF6. TRAF6 polyubiquitination is required for the activation of IRF7, presumably by promoting the phosphorylation and subsequent nuclear translocation of IRF7.

Publication

Ubiquitin Signaling in the NF-κB Pathway. () Zhijian J. Chen. Nat Cell Biol. ;7(8):758-765. Figure: F4. All organisms Danio rerio Homo sapiens

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