TRAF2: a double-edged sword?
Ubiquitination is best known for its role in targeting proteins for degradation by the proteasome, but evidence of the nonproteolytic functions of ubiquitin is also rapidly accumulating. One example of the regulatory, rather than proteolytic, function of ubiquitin is provided by study of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) proteins, which function as ubiquitin ligases to synthesize lysine 63 (K(63))-linked polyubiquitin chains to mediate protein kinase activation through a proteasome-independent mechanism. Some TRAF proteins, such as TRAF2 and TRAF3, have recently been shown to have a positive role in the canonical pathway that activates nuclear factor kappaB (NF-kappaB) through IkappaB kinase beta (IKKbeta), but a negative role in the noncanonical pathway that activates NF-kappaB through IKKalpha. These opposing roles of TRAF proteins may be linked to their ability to synthesize distinct forms of polyubiquitin chains. Indeed, the TRAF2-interacting protein RIP can mediate IKK activation when it is modified by K(63) polyubiquitin chains, but is targeted to degradation by the proteasome when it is K(48)-polyubiquitinted by the NF-kappaB inhibitor A20. Thus, ubiquitin chains are dynamic switches that can influence signaling outputs in dramatically different ways.
Xia
Zong-Ping
ZP
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Chen
Zhijian J
ZJ
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D016207:Cytokines / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D015398:Signal Transduction / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2 / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000502:physiology; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000502:physiology
D016207:Cytokines; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D025801:Ubiquitin; D051550:I-kappa B Kinase; D046988:Proteasome Endopeptidase Complex; D044764:Ubiquitin-Activating Enzymes