A complex interaction of signalling events, including the Wnt pathway, regulates sprouting of blood vessels from pre-existing vasculature during angiogenesis. Here we show that two distinct mutations in the (uro)chordate-specific gumby (also called Fam105b) gene cause an embryonic angiogenic phenotype in gumby mice. Gumby interacts with disheveled 2 (DVL2), is expressed in canonical Wnt-responsive endothelial cells and encodes an ovarian tumour domain class of deubiquitinase that specifically cleaves linear ubiquitin linkages. A crystal structure of gumby in complex with linear diubiquitin reveals how the identified mutations adversely affect substrate binding and catalytic function in line with the severity of their angiogenic phenotypes. Gumby interacts with HOIP (also called RNF31), a key component of the linear ubiquitin assembly complex, and decreases linear ubiquitination and activation of NF-κB-dependent transcription. This work provides support for the biological importance of linear (de)ubiquitination in angiogenesis, craniofacial and neural development and in modulating Wnt signalling.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931916 | PMC |
| http://dx.doi.org/10.1038/nature12296 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
TBK1-associated adapters TANK and AZI2 protect mice against TNF-induced cell death and severe autoinflammatory diseases.
Nat Commun
November 2024
Laboratory of Immunity & Cell Communication, Division BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic.
Article Synopsis
- The cytokine TNF can lead to a type of cell death influenced by RIPK1, but this can be suppressed by two proteins, TANK and AZI2, which help regulate TBK1 kinase activation.
- Mice lacking both TANK and AZI2 experience severe health issues like multi-organ inflammation and early death, which can be mitigated by disabling TNFR1 or using a modified RIPK1.
- TANK and AZI2 work together in the TNF receptor signaling process, binding to different components at distinct times to maintain TBK1 activity and protect against excessive inflammation.
OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice.
Nat Commun
October 2021
Institute for Genetics, University of Cologne, Cologne, Germany.
Linear ubiquitination regulates inflammatory and cell death signalling. Deficiency of the linear ubiquitin chain-specific deubiquitinase, OTULIN, causes OTULIN-related autoinflammatory syndrome (ORAS), a systemic inflammatory pathology affecting multiple organs including the skin. Here we show that mice with epidermis-specific OTULIN deficiency (OTULIN) develop inflammatory skin lesions that are driven by TNFR1 signalling in keratinocytes and require RIPK1 kinase activity.
View Article and Find Full Text PDFOTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity.
Nat Commun
October 2021
VIB Center for Inflammation Research, Ghent, Belgium.
OTULIN is a deubiquitinase that specifically cleaves linear ubiquitin chains. Here we demonstrate that the ablation of Otulin selectively in keratinocytes causes inflammatory skin lesions that develop into verrucous carcinomas. Genetic deletion of Tnfr1, knockin expression of kinase-inactive Ripk1 or keratinocyte-specific deletion of Fadd and Mlkl completely rescues mice with OTULIN deficiency from dermatitis and tumorigenesis, thereby identifying keratinocyte cell death as the driving force for inflammation.
View Article and Find Full Text PDFOTULIN Prevents Liver Inflammation and Hepatocellular Carcinoma by Inhibiting FADD- and RIPK1 Kinase-Mediated Hepatocyte Apoptosis.
Cell Rep
February 2020
VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. Electronic address:
Inflammatory signaling pathways are tightly regulated to avoid chronic inflammation and the development of disease. OTULIN is a deubiquitinating enzyme that controls inflammation by cleaving linear ubiquitin chains generated by the linear ubiquitin chain assembly complex. Here, we show that ablation of OTULIN in liver parenchymal cells in mice causes severe liver disease which is characterized by liver inflammation, hepatocyte apoptosis, and compensatory hepatocyte proliferation, leading to steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC).
View Article and Find Full Text PDFOTULIN limits cell death and inflammation by deubiquitinating LUBAC.
Nature
July 2018
Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
OTULIN (OTU deubiquitinase with linear linkage specificity) removes linear polyubiquitin from proteins that have been modified by LUBAC (linear ubiquitin chain assembly complex) and is critical for preventing auto-inflammatory disease and embryonic lethality during mouse development. Here we show that OTULIN promotes rather than counteracts LUBAC activity by preventing its auto-ubiquitination with linear polyubiquitin. Thus, knock-in mice that express catalytically inactive OTULIN, either constitutively or selectively in endothelial cells, resembled LUBAC-deficient mice and died midgestation as a result of cell death mediated by TNFR1 (tumour necrosis factor receptor 1) and the kinase activity of RIPK1 (receptor-interacting protein kinase 1).
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!