Regulation of the deubiquitinating enzyme CYLD by IkappaB kinase gamma-dependent phosphorylation.
Tumor suppressor CYLD is a deubiquitinating enzyme (DUB) that inhibits the ubiquitination of key signaling molecules, including tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2). However, how the function of CYLD is regulated remains unknown. Here we provide evidence that inducible phosphorylation of CYLD is an important mechanism of its regulation. Under normal conditions, CYLD dominantly suppresses the ubiquitination of TRAF2. In response to cellular stimuli, CYLD undergoes rapid and transient phosphorylation, which is required for signal-induced TRAF2 ubiquitination and activation of downstream signaling events. Interestingly, the CYLD phosphorylation requires IkappaB kinase gamma (IKKgamma) and can be induced by IKK catalytic subunits. These findings suggest that CYLD serves as a novel target of IKK and that the site-specific phosphorylation of CYLD regulates its signaling function.
Reiley
William
W
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, PA 17033, USA.
Zhang
Minying
M
Wu
Xuefeng
X
Granger
Erica
E
Sun
Shao-Cong
SC
D000595:Amino Acid Sequence; D020134:Catalytic Domain; D002460:Cell Line; D000074749:Deubiquitinating Enzyme CYLD; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000276:immunology / Q000494:pharmacology; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
D008934:Mitogens; D021122:Protein Subunits; D047992:TNF Receptor-Associated Factor 2; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D048031:JNK Mitogen-Activated Protein Kinases; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD