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Mouse heart proteomic analysis of CYLD-binding proteins

ABSTRACT: The peptide sequences identified by mass spectrometry in the proteins immunoprecipitated from the mouse ventricular lysate with the anti-CYLD antibody.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Wei Xie

LAB HEAD: Jun Zhou

PROVIDER: PXD038360 | Pride | 2023-01-16

REPOSITORIES: Pride

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	MS_identified_data.zip	Other
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Publications

CYLD deubiquitinates plakoglobin to promote Cx43 membrane targeting and gap junction assembly in the heart.

Xie Wei W Gao Siqi S Yang Yunfan Y Li Hongjie H Zhou Junyan J Chen Mingzhen M Yang Song S Zhang Yijun Y Zhang Liang L Meng Xiaoqian X Xie Songbo S Liu Min M Li Dengwen D Chen Yan Y Zhou Jun J

Cell reports 20221201 13

During heart maturation, gap junctions assemble into hemichannels and polarize to the intercalated disc at cell borders to mediate electrical impulse conduction. However, the molecular mechanism underpinning cardiac gap junction assembly remains elusive. Herein, we demonstrate an important role for the deubiquitinating enzyme cylindromatosis (CYLD) in this process. Depletion of CYLD in mice impairs the formation of cardiac gap junctions, accelerates cardiac fibrosis, and increases heart failure. ...[more]

PMID: 36577382

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Cyld CGH

Project description:In order to identify the function of the tumor suppressor CYLD in liver, we generate a liver specific disruption of this gene in mouse (liver specific CYLD KO mice). In our analysis it was revealed that these mice initially develop fibrosis and finally they develop spontaneous liver cancer after 1 year of age. We performed CGH analysis in 8 different tumor foci from the tumor livers of 4 different CYLD liver specific KO animals, in comparison to wild type reference liver DNA. From every tumor liver, two cancer foci was microdissected. Cancer foci samples with IDs: DS-071_01 and DS-071_02 are from liver specific CYLD KO animal #1, DS-071_03 and DS-071_04 are from liver specific CYLD KO animal #2, DS-071_05 and DS-071_06 are from liver specific CYLD KO animal #3, DS-071_07 and DS-071_08 are from liver specific CYLD KO animal #4. Liver genomic DNA from cancer samples and from a reference wild type liver was extracted (Qiagen) and CGH analysis was performed to determine DNA copy number changes (IMGM Laboratories, Germany). This analysis revealed a large number of amplifications and deletions ranging from 0,62Mb to 14,8Mb in all chromosomes.

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Gene expression profiling of SAS cell line transfected with siRNA targeting CYLD

Project description:Oral squamous cell carcinoma (OSCC) has a very poor prognosis due to its highly invasive nature, and 5-year survival rate has not changed apparently for the past 30 years. Although cylindromatosis (CYLD) is thought as a potent tumor suppressor, its biological and clinical significances in OSCC are largely unknown. The aim of this study was to clarify roles of CYLD in OSCC progression. Our immunohistochemical analyses revealed that CYLD expression was significantly reduced at invasive lesions in OSCC tissues whereas it was conserved in normal epithelium and carcinoma in situ. Accordingly, downregulation of CYLD by siRNA led to an acquisition of mesenchymal state and increased migratory and invasive activities in OSCC cells and HaCaT keratinocytes. Interestingly, CYLD knockdown promoted TGF-beta signaling by inducing TGF-beta receptor I (ALK5) stabilization in a cell autonomous fashion. In addition, the response to exogenous TGF-beta stimulation was enhanced by CYLD downregulation. The invasive phenotype induced by CYLD knockdown were completely blocked by an ALK5 inhibitor. Furthermore, lower CYLD expression was significantly associated with deep invasion, poor overall survival, and increased Smad3 phosphorylation which is an indicator of TGF-beta signaling activation in invasive OSCC. These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells.

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Inactivation of tumor suppressor CYLD inhibits fibroblast re-programming to pluripotency

Project description:CYLD is a tumor suppressor gene coding for a deubiquitinating enzyme that has a critical regu-latory function in a variety of signaling pathways and biological processes involved in cancer development and progression, many of which are also key modulators of somatic cell repro-gramming. Nevertheless, the potential role of CYLD in this process has not been studied. With the dual aim of investigating the involvement of CYLD in reprogramming and better under-standing the intricate regulatory system governing this process, we reprogrammed control (CYLDWT/WT ) and CYLD-deficient (CYLDΔ9/Δ9 ) Mouse Embryonic Fibroblasts (MEFs) into induced Pluripotent Stem Cells (iPSCs) through ectopic overexpression of the Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc) . CYLD deficiency led to significantly reduced reprogramming efficiency and slower early reprogramming kinetics. Nevertheless, CYLD-deficient cells were capable of estab-lishing pluripotent colonies with full spontaneous differentiation potential. The introduction of WT CYLD to CYLDΔ9/Δ9 MEFs rescued the phenotype. Whole proteome analysis revealed that the Mesenchymal to Epithelial transition (MET) during the early stages of reprogramming was dis-rupted in CYLDΔ9/Δ9 MEFs. Interestingly, pathway analysis revealed that the primary processes affected by CYLD deficiency were associated with the extracellular matrix and several metabolic pathways. Our findings not only establish CYLD's significance as a regulatory component of early reprogramming but also highlight its role as an extracellular matrix regulator, which has profound implications in cancer research.

2023-11-21 | PXD044220 | Pride

Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains

Project description:Non-degradative ubiquitin chains and phosphorylation events govern signaling responses by innate immune receptors. The deubiquitinase CYLD in complex with SPATA2 is recruited to receptor signaling complexes by the ubiquitin ligase LUBAC and regulates Met1- and Lys63-linked polyubiquitin and receptor signaling outcomes. Here, we investigated the molecular determinants of CYLD activity. We reveal that two CAP-Gly domains in CYLD are ubiquitin binding domains and demonstrate a requirement of CAP-Gly3 for CYLD activity and regulation of immune receptor signaling. Moreover, we identify a phosphorylation switch outside of the catalytic USP domain, which activates CYLD selectively towards Lys63-linked polyubiquitin. The phosphorylated residue Ser568 is a novel TNF-regulated phosphorylation site in CYLD and works in concert with Ser418 to enable CYLD-mediated deubiquitination and immune receptor signaling. We propose that phosphorylated CYLD together with SPATA2 and LUBAC functions as a ubiquitin-editing complex that rebalances Lys63- and Met1-linked polyubiquitin at receptor signaling complexes, resulting in escalated LUBAC signaling.

2021-11-02 | PXD026791 | Pride

EGF-dependent ubiquitinome, phosphorylation and interactome analysis in control and CYLD-deficient cells

Project description:Cylindromatosis tumor suppressor protein (CYLD) is deubiquitinase, best known as an essential negative regulator of the NFkB pathway. Previous studies have suggested an involvement of CYLD in epidermal growth factor (EGF)-dependent signal transduction as well, as it was found enriched within the tyrosine-phosphorylated complexes in cells stimulated with the growth factor. EGF receptor (EGFR) signaling participates in central cellular processes and its tight regulation, partly through ubiquitination cascades, is decisive for a balanced cellular homeostasis. Here, using a combination of mass spectrometry-based quantitative proteomic approaches with biochemical and immunofluorescence strategies, we demonstrate the involvement of CYLD in the regulation of the ubiquitination events triggered by EGF. Our data show that CYLD regulates the magnitude of ubiquitination of several major effectors of the EGFR pathway by assisting the recruitment of the ubiquitin ligase Cbl-b to the activated EGFR complex. Notably, the deficiency of CYLD impairs the interaction of EGFR with Cbl-b, which leads to a reduced ubiquitination of the receptor followed by its decreased degradation. This represents a previously uncharacterized strategy exerted by this deubiquitinase and tumors pressor for the negative regulation of a tumorigenic signaling pathway.

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EGF-dependent ubiquitinome, phosphorylation and interactome analysis in control and CYLD-deficient cells

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