Ubiquitin signaling in immune cell function and ageing

1 PhD project offered in the IPP summer call 2021

This project is part of the Science of Healthy Ageing Research Programme (SHARP).

Scientific background

Chronic inflammation is a source of many ageing-related problems, including cancer, obesity, cardiovascular and neurological diseases. Therefore, proper control of the pro-inflammatory NF-κB signaling pathway is key to preventing premature ageing. A major regulator of this pathway is the ubiquitin system. Ubiquitin as a posttranslational modifier is known for inducing protein degradation, but also acts in many non-proteolytic ways by modulating the localization or interactions of its targets. In this context, polyubiquitin chains of a dedicated geometry, where the ubiquitin units are linked to each other via lysine (K) 63, feature prominently.

One of the key components of the ubiquitin system controlling the NF-κB pathway is encoded by the tumor suppressor gene CYLD that is mutated in familial cylindromatosis, an autosomal dominant predisposition to multiple tumors of the skin appendages. The CYLD gene encodes a deubiquitylating enzyme that removes K63-linked ubiquitin chains from IκB kinase signaling components and thereby inhibits NF-κB signaling. Mutations of Cyld in mice result in high susceptibility to tumor development and inflammatory diseases. The relevance of CYLD as an anti-ageing factor is underscored by the finding that mutations in Cyld are associated with enhanced ageing in mice. The Waisman lab has identified a short splice variant of CYLD (sCYLD) that is overexpressed in some lymphomas. Mice expressing exclusively and excessively sCYLD (termed CYLDex7/8 mice) exhibit various abnormalities including immune malfunction of B cells, T cells and dendritic cells. Importantly, exclusive expression of sCYLD in the absence of full-length CYLD (flCYLD), pre-disposes mice to develop lymphomas, but its role in ageing is not yet known.

PhD project: Role of the deubiquitylating enzyme CYLD in immune cell function and ageing     

This PhD project will be carried out as a collaboration of the Waisman lab with their strong expertise in genetics and immunology with the Ulrich lab, who will contribute expertise in the molecular biology of the ubiquitin system. Its objective is to elucidate the relevance of sCYLD to ageing. The PhD student will analyze mice with a complete CYLD deficiency as well as CYLDex7/8 mice for age-related manifestations that could be enhanced with hyper-activation of the NF-κB pathway. On the molecular level, the student will analyze how sCYLD differs from flCYLD in function and binding to relevant deubiquitylation targets. In addition, they will analyze the signaling complexes involved in the NF-κB pathway to understand how flCYLD and sCYLD regulate the NF-κB pathway. The student will be jointly supervised by Ari Waisman and Helle Ulrich and will work in both labs.

If you are interested in this project, please select Ari Waisman as your group preference in the IPP application platform.

Publications relevant to the project

Hahn M, Burckert JP, Luttenberger CA, Klebow S, Hess M, Al-Maarri M, Vogt M, Reissig S, Hallek M, Wienecke-Baldacchino A, Buch T, Muller CP, Pallasch CP, Wunderlich FT, Waisman A and Hovelmeyer N (2018) Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic lymphocytic leukemia via sustained NF-kappaB signaling. Leukemia, 32:72-82 Link

Tang Y, Reissig S, Glasmacher E, Regen T, Wanke F, Nikolaev A, Gerlach K, Popp V, Karram K, Fantini MC, Schattenberg JM, Galle PR, Neurath MF, Weigmann B, Kurschus FC, Hovelmeyer N and Waisman A (2019) Alternative Splice Forms of CYLD Mediate Ubiquitination of SMAD7 to Prevent TGFB Signaling and Promote Colitis. Gastroenterology, 156:692-707 e7 Link

Takahashi TS, Wollscheid HP, Lowther J and Ulrich HD (2020) Effects of chain length and geometry on the activation of DNA damage bypass by polyubiquitylated PCNA. Nucleic Acids Res, 48:3042-3052 Link

Renz C, Albanèse V, Tröster V, Albert TK, Santt O, Jacobs SC, Khmelinskii A, Léon S and Ulrich HD (2020) Ubc13-Mms2 cooperates with a family of RING E3 proteins in budding yeast membrane protein sorting. J Cell Sci, 133:jcs244566 Link

Contact

Prof. Ari Waisman (If you are interested in this project, please select Ari Waisman as your group preference in the IPP application platform.)

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Prof. Helle Ulrich

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