Universität zu Köln

Betrancourt, Alexis ORCID: 0009-0008-5365-9454 (2023). Characterisation of ANKIB1 as a new regulator of Toll-Like Receptor signalling. PhD thesis, Universität zu Köln.

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Abstract

Interferon production triggered by the stimulation of the Pattern-Recognition-Receptors (PRR) following infection is primordial to induce an efficient immune response and prevent dramatic consequences for the host. Toll-Like Receptors (TLRs) play a crucial role in this process. Via TRIF, TLR3 and TLR4 are able to recruit IRF3 to the signalling complexes, thereby promoting its activation by TBK1. This latter is a crucial kinase involved in several immune signalling such as TNF, NOD, and TLRs where it contributes to the regulation of cell death or induces interferon production. However, its recruitment and activation to these receptors depend on different proteins, and post-translational modifications such as ubiquitination are primordial. In TNF pathway, TBK1 activation and recruitment to the TNF Receptor 1 Signalling Complex (TNFR1-SC) requires the presence of HOIP. This latter generates linear ubiquitin chains which are primordial to link NEMO to TBK1 via the adaptor molecules TANK and NAP1. On the other hand, in TLR3 pathway where TBK1 is required to induce type I and type III interferon, the presence of HOIP is not required suggesting that another E3 ligase is implicated in this process. However, this ubiquitin E3 is still not known. In this study, we have identified ANKIB1 as a new regulator of TBK1 activation in TLR3. The absence of this E3 ligase impairs TBK1 phosphorylation and, consequently, IRF3 activation, the transcription factor that mediates interferon production. Following TLR3 stimulation, ANKIB1 is recruited to TLR3-Signalling Complex (TLR3-SC) and interacts with TBK1, optineurin, and NEMO. Oppositely, ANKIB1 is not recruited to TNFR1-SC, therefore, is not involved in this signalling pathway. In order to promote TBK1 activation, ANKIB1 requires its catalytic activity which generates K11 and K63 ubiquitin chains. It also requires its UIM domain, which confers the ability to interact with ubiquitinated proteins. ANKIB1 is also involved in TBK1 and IRF3 phosphorylation in TRIF-mediated TLR4 signalling, but not by Myd88. Consequently, ANKIB1 is primordial to induce type I and type III interferon production following TLR3 and TLR4 stimulation. In summary, the results of this thesis identify ANKIB1 as a new member of TLR signalling pathways, which via its catalytic activity, contributes to the phosphorylation of TBK1 and consequently to the production of interferon-mediated by IRF3.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Betrancourt, Alexis UNSPECIFIED https://orcid.org/0009-0008-5365-9454 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-800755
Date:	2023
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Natural sciences and mathematics
Uncontrolled Keywords:	Keywords Language Pattern Recognition Receptors UNSPECIFIED Interferon pathways UNSPECIFIED Ubiquitination UNSPECIFIED E3 ligase UNSPECIFIED
Date of oral exam:	14 August 2023
Referee:	Name Academic Title Walczak, Henning Prof.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80075