The molecular mechanism by which TRAF6 regulates the immune system (360G-Wellcome-209380_Z_17_Z)

£2,299,918

TRAF6 is essential for many biological processes, including those activated by interleukin-1 (IL-1) family members, Toll-Like-Receptor (TLR) ligands, and TNF superfamily (TNFSF) members. We have unexpectedly discovered that many of the essential roles of TRAF6 are independent of its E3 ubiquitin ligase activity and that, surprisingly, a key role of the TRAF6 E3 ligase is to restrict T cell activation and prevents autoimmunity. Building on these and other exciting findings we have made, the aim of the proposed reseach is to solve three major questions:- 1.What are the molecular mechanisms by which TRAF6 mediates signaling by the TNF superfamily members RANKL, CD40 and BAFF? 2. What are the molecular mechanisms by which the TRAF6 E3 ligase restricts T cell activation, and will they open up new opportunities to unleash the power of cytotoxic T cells to treat cancers and other diseases? 3. How does the TRAF6 E3 ligase activate a novel IL-1-dependent signaling pathway we have identified, which triggers activation of the "master" kinase TAK1 in the absence of its ubiquitin-binding subunits TAB2 and TAB3, and does this pathway have important roles in other TRAF6-dependent processes?

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Grant Details

Amount Awarded 2299918
Applicant Surname Cohen
Approval Committee Science Interview Panel
Award Date 2017-11-28T00:00:00+00:00
Financial Year 2017/18
Grant Programme: Title Investigator Award in Science
Internal ID 209380/Z/17/Z
Lead Applicant Prof Sir Philip Cohen
Partnership Value 2299918
Planned Dates: End Date 2024-04-01T00:00:00+00:00
Planned Dates: Start Date 2018-04-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Scotland