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OTULINVIVO

The role of OTULIN and Met1-linked ubiquitin in immune signaling and host defense in vivo

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EC-Contrib. €

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Project "OTULINVIVO" data sheet

The following table provides information about the project.

Coordinator
UNITED KINGDOM RESEARCH AND INNOVATION 

There are not information about this coordinator. Please contact Fabio for more information, thanks.

 Coordinator Country United Kingdom [UK]
 Project website http://www2.mrc-lmb.cam.ac.uk/major-breakthrough-identifies-cause-treatment-fatal-autoimmune-disease/
 Total cost 183˙454 €
 EC max contribution 183˙454 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2014
 Funding Scheme MSCA-IF-EF-ST
 Starting year 2015
 Duration (year-month-day) from 2015-04-01   to  2017-03-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    UNITED KINGDOM RESEARCH AND INNOVATION UK (SWINDON) coordinator 183˙454.00
2    MEDICAL RESEARCH COUNCIL UK (SWINDON) coordinator 0.00

Map

 Project objective

The immune system is essential for host defense against infections. Methionine1-linked ‘linear’ ubiquitin chains (Met1-Ub) have emerged as a crucial activator of NF-κB transcription factors, which are vital to immune responses. Recent findings suggest that defects in Met1-Ub signaling in humans can lead to severe immune dysfunction and cancer. Met1-Ub is generated by the linear ubiquitin chain assembly complex (LUBAC). Yet, how LUBAC and Met1-Ub signaling are regulated remains elusive. We recently discovered OTULIN, the only deubiquitinase known to specifically disassemble Met1-Ub. OTULIN antagonizes LUBAC and restricts Met1-Ub and NF-κB signaling in cell culture; however, the role of OTULIN and Met1-Ub in immune signaling and host defense in vivo is largely unknown. We have established novel mouse strains with cell type-specific deletion of OTULIN. I will use these mice to explore the in vivo function of OTULIN and Met1-Ub in the innate and adaptive immune responses, and to identify OTULIN substrates in primary cells using state-of-the-art mass spectrometry-based proteomics. I will study OTULIN’s role in immune homeostasis, in response to bacterial infection, and in mounting type-1 and type-2 adaptive immune responses by state-of-the-art methods of immunological analyses including comprehensive multiplex analyses of cytokines. Met1-Ub regulates the acute phase cytokines TNF and IL-6 and may thus control the development of type-1 versus type-2 immune responses. Hence, I will test OTULIN’s role in models of asthma, a disorder characterized by an imbalance between type-1 and type-2 responses. Subsequently, I will analyze immune signaling pathways in primary cells using mass spectrometry-based proteomics to identify OTULIN substrates in specific cell types. This will greatly deepen our understanding of the physiological role of OTULIN and Met1-Ub in the immune response and may provide important insight into human immunological disorders and rationales to treat these.

 Publications

year authors and title journal last update
List of publications.
2016 Rune Busk Damgaard, Jennifer A. Walker, Paola Marco-Casanova, Neil V. Morgan, Hannah L. Titheradge, Paul R. Elliott, Duncan McHale, Eamonn R. Maher, Andrew N.J. McKenzie, David Komander
The Deubiquitinase OTULIN Is an Essential Negative Regulator of Inflammation and Autoimmunity
published pages: 1215-1230.e20, ISSN: 0092-8674, DOI: 10.1016/j.cell.2016.07.019
Cell 166/5 2019-07-22

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