Редактирование: CYLD

Ubiquitin carboxyl-terminal hydrolase CYLD (EC 3.4.19.12) (Deubiquitinating enzyme CYLD) (Ubiquitin thioesterase CYLD) (Ubiquitin-specific-processing protease CYLD) [CYLD1] [KIAA0849] [HSPC057]

==Publications==

{{medline-entry
|title=Premature aging and cancer development in transgenic mice lacking functional [[CYLD]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30631004
|abstract=[[CYLD]] is a deubiquitinating enzyme known for its role as a tumor suppressor whose mutation leads to skin appendages tumors and other cancers. In this manuscript we report that the tumor suppressor [[CYLD]], similarly to other renowned tumor suppressor genes, protects from premature aging and cancer. We have generated transgenic mice expressing the mutant [[CYLD]]  protein, lacking its deubiquitinase function, under the control of the keratin 5 promoter, the K5-[[CYLD]]  mice. These mice express the transgene in different organs, including those considered to be more susceptible to aging, such as skin and thymus. Our results show that K5-[[CYLD]]  mice exhibit epidermal, hair follicle, and sebaceous gland alterations; and, importantly, they show signs of premature aging from an early age. Typically, 3-month-old K5-[[CYLD]]  mice exhibit a phenotype characterized by alopecia and kyphosis, and, the histological examination reveals that transgenic mice show signs of accelerated aging in numerous organs such as skin, thymus, pancreas, liver and lung. Additionally, they spontaneously develop tumors of diverse origin. Over-activation of the NF-κB pathway, along with hyperactivation of Akt, JNK and c-Myc, and chronic inflammation, appear as the mechanisms responsible for the premature aging of the K5-[[CYLD]]  mice.
|mesh-terms=* Aging, Premature
* Animals
* Cell Line
* Cyclin-Dependent Kinase Inhibitor p16
* Deubiquitinating Enzyme CYLD
* Gene Expression Regulation
* Hair Follicle
* Humans
* Keratinocytes
* Mice
* Mice, Transgenic
* Mutation
* NF-kappa B
* Neoplasms
* Promoter Regions, Genetic
* Skin Aging
* Thymus Gland
* Tumor Necrosis Factor-alpha
|keywords=* CYLD
* NF-κB
* inflammation
* keratinocyte differentiation
* premature aging
* skin
* tumor suppressor
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339805
}}
{{medline-entry
|title=Pathophysiological significance of cylindromatosis in the vascular endothelium and macrophages for the initiation of age-related atherogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30554661
|abstract=Cardiovascular disease is one of the leading causes of death in the elderly, and novel therapeutic targets against atherogenesis are urgent. The initiation of atherosclerotic changes of monocyte adhesion on the vascular endothelium and subsequent foam cell formation are noteworthy pathophysiologies when searching for strategies to prevent the progression of age-related atherosclerosis. We report the significance of the deubiquitinating enzyme cylindromatosis ([[CYLD]]) in vascular remodeling by interference with inflammatory responses regulated by NF-κB signaling. The purpose of this study was to elucidate the pathological functions of [[CYLD]] in the early phase of atherogenesis associated with aging. Treatment with inflammatory cytokines induced endogenous [[CYLD]] in aortic endothelial cells (HAECs) and THP-1 cells. siRNA-mediated [[CYLD]] silencing led to enhanced monocyte adhesion along with increased adhesion molecules in HAECs treated with TNFα. In siRNA-mediated [[CYLD]] silenced RAW 264.7 macrophages treated with oxidized LDL (oxLDL), augmented lipid accumulation was observed, along with increased expression of the class A macrophage scavenger receptor (SR-A), lectin-like oxidized LDL receptor-1 (LOX-1), [[CD36]], fatty acid binding protein 4 (FABP4), the cholesterol ester synthase acyl-CoA cholesterol acyltransferase (ACAT1), MCP-1, and IL-1β and decreased expression of scavenger receptor class B type I (SR-BI). Intriguingly, [[CYLD]] gene expression was significantly reduced in bone marrow-derived macrophages of aged mice compared that of young mice, as well as in senescent HAECs compared with young cells. These findings suggest that age-related attenuation of [[CYLD]] expression in endothelial cells (ECs) and macrophages triggers the initiation of age-related atherogenesis by exacerbating monocyte adhesion on the endothelium and foam cell formation. [[CYLD]] in the vasculature may be a novel therapeutic target, especially in the early preventive intervention against the initiation of age-related atherogenesis.
|mesh-terms=* Aging
* Animals
* Atherosclerosis
* Bone Marrow Cells
* Cell Adhesion
* Cysteine Endopeptidases
* Cytokines
* Deubiquitinating Enzyme CYLD
* Endothelial Cells
* Endothelium, Vascular
* Foam Cells
* Gene Silencing
* Humans
* Inflammation Mediators
* Lipoproteins, LDL
* Macrophages
* Male
* Mice
* RAW 264.7 Cells
* RNA, Small Interfering
* THP-1 Cells
* Up-Regulation
|keywords=* Aging
* CYLD
* Endothelial cell
* Foam cell
* Inflammation
* Macrophage
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2018.12.025
}}
{{medline-entry
|title=Elevated A20 contributes to age-dependent macrophage dysfunction in the lungs.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24440463
|abstract=Advanced age is associated with chronic low-grade inflammation (i.e. inflamm-aging) and poor macrophage function that includes a weak pro-inflammatory cytokine response to bacteria and diminished phagocytosis (i.e. age-dependent macrophage dysfunction [ADMD]). One reason for this is that ADMD is associated with poor NFκB and MAPK activation following Toll-like receptor stimulation. Herein, we tested the hypothesis that inflamm-aging induces production of A20, a cytosolic and homeostatic suppressor of the NFκB and MAPK signaling cascades that deubiquitinates (i.e. inactivates) the common upstream signaling molecule [[TRAF6]], and this is responsible for ADMD. Western blots and immunohistochemistry comparing tissues from young, mature, and aged C57BL/6 mice indicated that A20 was strongly elevated in the lungs of aged mice but not in other tissues. Elevated A20 was also detected in alveolar macrophages (AM) from aged mice. In contrast [[CYLD]], a second deubiquitinase that also negatively regulates the NFκB pathway was decreased with aging. Following co-incubation of AM with the bacteria Streptococcus pneumoniae, [[TRAF6]] polyubiquitination was diminished in AM isolated from aged versus young mice. A20 production was inducible in the J774A.1 macrophage cell line and C57BL/6AM by overnight incubation with TNFα but not IL-6. Retrovirus-induced expression of A20 in J774A.1 cells resulted in their diminished production of IL-6 following exposure to S. pneumoniae but had no effect on levels of phagocytosis. Overnight incubation of AM from young mice with TNFα also resulted in a dampened IL-6 response to S. pneumoniae. Finally, dietary supplementation of aged mice with anti-inflammatory n-3 polyunsaturated fatty acids in the form of fish oil lowered lung A20 levels and enhanced resistance, including a 100-fold reduction in bacterial titers in the lungs, to experimental challenge with S. pneumoniae. We conclude that elevated A20 due to TNFα partially explains the ADMD phenotype and that ADMD is potentially reversible. 
|mesh-terms=* Animals
* Anti-Inflammatory Agents
* Cells, Cultured
* Cellular Senescence
* Cysteine Endopeptidases
* Cytokines
* Female
* Fish Oils
* Immunity, Innate
* Intracellular Signaling Peptides and Proteins
* Lung
* Macrophages, Alveolar
* Mice, Inbred C57BL
* NF-kappa B
* Phagocytosis
* Pneumococcal Infections
* Pneumonia, Bacterial
* Streptococcus pneumoniae
* TNF Receptor-Associated Factor 6
* Tumor Necrosis Factor alpha-Induced Protein 3
* Tumor Necrosis Factor-alpha
* Ubiquitination
|keywords=* Aging
* Infection
* Inflammation
* Innate immunity
* Macrophage
* Pneumonia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989429
}}
{{medline-entry
|title=Tumor suppressor [[CYLD]] regulates JNK-induced cell death in Drosophila.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/17765686
|abstract=[[CYLD]] encodes a tumor suppressor that is mutated in familial cylindromatosis. Despite biochemical and cell culture studies, the physiological functions of [[CYLD]] in animal development and tumorigenesis remain poorly understood. To address these questions, we generated Drosophila [[CYLD]] (d[[CYLD]]) mutant and transgenic flies expressing wild-type and mutant d[[CYLD]] proteins. Here we show that d[[CYLD]] is essential for JNK-dependent oxidative stress resistance and normal lifespan. Furthermore, d[[CYLD]] regulates [[TNF]]-induced JNK activation and cell death through dTRAF2, which acts downstream of the [[TNF]] receptor Wengen and upstream of the JNKK kinase dTAK1. We show that d[[CYLD]] encodes a deubiquitinating enzyme that deubiquitinates dTRAF2 and prevents dTRAF2 from ubiquitin-mediated proteolytic degradation. These data provide a molecular mechanism for the tumor suppressor function of this evolutionary conserved molecule by indicating that d[[CYLD]] plays a critical role in modulating [[TNF]]-JNK-mediated cell death.
|mesh-terms=* Animals
* Animals, Genetically Modified
* Apoptosis
* Cell Death
* Deubiquitinating Enzyme CYLD
* Drosophila
* Drosophila Proteins
* Genes, Insect
* Genes, Tumor Suppressor
* JNK Mitogen-Activated Protein Kinases
* Longevity
* Mutation
* Oxidative Stress
* Plasmids
* Precipitin Tests
* Signal Transduction
* TNF Receptor-Associated Factor 2
* Tumor Suppressor Proteins

|full-text-url=https://sci-hub.do/10.1016/j.devcel.2007.07.012
}}