title: CYLD and the NEMO Zinc Finger Regulate Tumor Necrosis Factor Signaling and Early Embryogenesis.
abstract: NF-κB essential modulator (NEMO) and cylindromatosis protein (CYLD) are intracellular proteins that regulate the NF-κB signaling pathway. Although mice with either CYLD deficiency or an alteration in the zinc finger domain of NEMO (K392R) are born healthy, we found that the combination of these two gene defects in double mutant (DM) mice is early embryonic lethal but can be rescued by the absence of TNF receptor 1 (TNFR1). Notably, NEMO was not recruited into the TNFR1 complex of DM cells, and consequently NF-κB induction by TNF was severely impaired and DM cells were sensitized to TNF-induced cell death. Interestingly, the TNF signaling defects can be fully rescued by reconstitution of DM cells with CYLD lacking ubiquitin hydrolase activity but not with CYLD mutated in TNF receptor-associated factor 2 (TRAF2) or NEMO binding sites. Therefore, our data demonstrate an unexpected non-catalytic function for CYLD as an adapter protein between TRAF2 and the NEMO zinc finger that is important for TNF-induced NF-κB signaling during embryogenesis.
authors.affiliation: From the Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, Maryland 20892, yongge.zhao@nih.gov.
authors.forename: Yongge
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: From the Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Chi A
authors.initials: CA
authors.lastname: Ma
authors.affiliation: From the Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Liming
authors.initials: L
authors.lastname: Wu
authors.affiliation: the Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iwai
authors.affiliation: the Laboratory of Immune Cell Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Ashwell
authors.affiliation: the Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, and.
authors.forename: Eugene M
authors.initials: EM
authors.lastname: Oltz
authors.affiliation: the Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232.
authors.forename: Dean W
authors.initials: DW
authors.lastname: Ballard
authors.affiliation: From the Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, Maryland 20892, ashish.jain1@merck.com.
authors.forename: Ashish
authors.initials: A
authors.lastname: Jain
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D047108:Embryonic Development / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D016335:Zinc Fingers / Q000235:genetics; D000074749:Deubiquitinating Enzyme CYLD
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD
keywords: CYLD; NEMO; NF-κB (NF-KB); cell signaling; immunodeficiency; protein complex; tumor necrosis factor (TNF)