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Deciphering the ubiquitin code of the TNF receptor signalling complex and its functional role in inflammation and immunity

Objective

Tumour necrosis factor (TNF) is a cytokine with important functions in inflammation, immunity and cancer. Signalling processes mediated by ubiquitin are crucial for TNF signalling. The seven lysine (K) residues and the N-terminus of ubiquitin can be used to form ubiquitin chains. Employing a method newly developed in our laboratory we identified the presence of four of these ubiquitin chain linkage types in the native TNF receptor signalling complex (TNF-RSC). Our knowledge of the specific functions of the different ubiquitin linkages is currently very limited. However, their presence in the TNF-RSC, combined with our recent technological advance in dissecting the composition of this protein complex with previously unreached specificity and sensitivity provides a unique opportunity for the proposed research programme: to molecularly and functionally decipher the ubiquitin code. We will aim to achieve this by studying the different ubiquitin chain linkages at the molecular level within the TNF-RSC and by determining how perturbation of specific ubiquitin linkage events impacts the physiological role of TNF in immunity to infection and its pathological function in inflammation-induced cancer.
The specific objectives of this project are:
• to molecularly decipher the ubiquitin code of the TNF-RSC (objective 1),
• to link this code to physiological functions of TNF in immunity to infection (objective 2)
• and to test its pathological impact on cancer-related inflammation (objective 3).

Field of science

  • /medical and health sciences/clinical medicine/cancer

Call for proposal

ERC-2011-ADG_20110310
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant
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Host institution

University College London
Address
Gower Street
WC1E 6BT London
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 760 601,26
Principal investigator
Henning Walczak (Prof.)
Administrative Contact
Giles Machell (Mr.)

Beneficiaries (2)

University College London
United Kingdom
EU contribution
€ 1 760 601,26
Address
Gower Street
WC1E 6BT London
Activity type
Higher or Secondary Education Establishments
Principal investigator
Henning Walczak (Prof.)
Administrative Contact
Giles Machell (Mr.)
IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE

Participation ended

United Kingdom
EU contribution
€ 606 735,74
Address
South Kensington Campus Exhibition Road
SW7 2AZ London
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Tatjana Palalic (Ms.)