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Title: The role of HOIL-1, HOIP and SHARPIN in immune signalling
Author: Rieser, Eva
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Members of the tumour necrosis factor receptor (TNFR) superfamily, the interleukin-1 Receptor (IL-1R), the Toll-like Receptor (TLR) and the NOD-like receptor (NLRs) families play crucial roles in the initiation of innate immune responses. Even though the stimulation of these different receptors is triggered by upstream signalling components which are largely receptor-specific, their signalling cascades generally converge in the activation of both mitogen-activated protein kinases (MAPKs) and the inhibitor of nuclear factor– B (I B) kinases (IKKs). The activation of MAPKs and IKKs are crucial events in the signalling cascades of TNFR-, IL-1R-, TLR- and NLR family members and result in the activation of distinct transcription factors such as AP-1 and NF- B, respectively. In order to gain a more comprehensive picture of the signalling components associated with TNFR1 our group developed a modified tandem affinity purification (moTAP) strategy. This led to the identification of three novel components of the native TNFR1 signalling complex (TNFRSC): HOIL-1, HOIP and SHARPIN. Together, they form the “linear ubiquitin chain assembly complex” (LUBAC), a tripartite E3 ligase complex which generates linear ubiquitin chains. LUBAC activity is required for efficient TNF-mediated activation of NF- B and JNK by linearly ubiquitinating NEMO and RIP1 in the TNF-RSC. Mutation of the SHARPIN-encoding gene in mice results in chronic proliferative dermatitis (cpdm). The cpdm phenotype is characterised by inflammatory skin lesions and defective lymphoid organogenesis. In this thesis it is shown that mouse embryonic fibroblasts (MEFs) and primary keratinocytes generated from cpdm mice showed impaired activation of the MAPK- and NF- B signalling pathways following stimulation by various TNF and IL-1 family members as well as by different TLR ligands. These alterations were also apparent in bone marrow-derived macrophages isolated from cpdm mice. Thereby, lack of SHARPIN exerted an inhibitory effect on gene-activatory signal transduction by these immune stimuli. Similar defects in NF- B and MAPK signalling were also observed with a ligand for the NLR family member NOD2. Cells generated from mice conditionally deficient for the other LUBAC components exhibited similar alterations in diverse innate immune signalling pathways. These results imply that SHARPIN and HOIL-1 cannot substitute each other but instead cooperate with HOIP to generate linear ubiquitin chains in the signalling pathways that are activated by diverse immune receptors. In summary, the results of this thesis identify LUBAC and the linear ubiquitin chains it generates as previously unrecognised components of various signalling pathways which are central to the induction of immunity and regulation of inflammation.
Supervisor: Walczak, Henning ; Screaton, Gavin Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available