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

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.

Coordinator

UNITED KINGDOM RESEARCH AND INNOVATION
Net EU contribution
€ 183 454,80
Address
Polaris House North Star Avenue
SN2 1FL Swindon
United Kingdom

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Region
South West (England) Gloucestershire, Wiltshire and Bristol/Bath area Swindon
Activity type
Research Organisations
Non-EU contribution
€ 0,00