Exploring ubiquitin and ISG15 biology with chemical tools

Gan, J. (2022)

Doctoral Thesis

Proteins play an essential role in almost all the processes of a living organism, and post-translational modifications (PTM) can regulate their structure, location, function, and fate. Ubiquitin and ISG15 are two of the most versatile and common PTM modifiers in mammalian cells. Aberrant modification of Ubiquitin and ISG15 in cells results in various diseases, such as cancers and microbial infections. This dissertation introduces the development of small-molecule inhibitors against ISG15 deconjugating enzyme USP18 and ubiquitin deconjugating enzyme OTUB2 separately, and the identification of USP16 as a dual deconjugating enzyme that cleaves Ubiquitin and ISG15 from substrates. These research achievements are supposed to deepen the understanding of biology, regulation, and biochemical mechanisms of Ubiquitin and ISG15 deconjugating enzymes, thus paving the way for deconjugating enzymes-targeted therapeutics development in the future.

• Ubiquitin
• ISG15
• Proteasome
• Activity-based probe
• Small-molecule inhibitor
• OTUB2
• USP18
• USP16

• All authors: Gan, J.
• Supervisor: Ovaa, H.; Neefjes. J.J.C.
• Co-supervisor: Sapmaz, A.; Geurink, P.P.
• Committee: Overkleeft, H.S.; Vertegaal, A.C.O.; Kessler, B.M.; Knobeloch, K.P.; Van der Veen, A.G.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2022-06-07
• ISBN (print): 9789493289055