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. Fields of science medical and health sciencesclinical medicinerheumatologymedical and health sciencesclinical medicinegastroenterologyinflammatory bowel diseasemedical and health sciencesclinical medicinecritical care medicinemedical and health sciencesbasic medicineneurologymultiple sclerosismedical and health sciencesbasic medicineimmunology Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2014-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Call for proposal H2020-MSCA-IF-2014 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator UNITED KINGDOM RESEARCH AND INNOVATION Net EU contribution € 183 454,80 Address POLARIS HOUSE NORTH STAR AVENUE SN2 1FL Swindon United Kingdom See on map Region South West (England) Gloucestershire, Wiltshire and Bristol/Bath area Swindon Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 183 454,80