Exploring ubiquitin and ISG15 biology with chemical tools

Author(s):
Gan, J.
Published
2022
Publication type
Doctoral Thesis

Abstract

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.

UbiquitinISG15ProteasomeActivity-based probeSmall-molecule inhibitorOTUB2USP18USP16
Defense date
2022-06-07
Language
English
Supervisor(s)
Ovaa, H.; Neefjes. J.J.C.
Advisor(s)
Sapmaz, A.; Geurink, P.P.
Committee member(s)
Overkleeft, H.S.; Vertegaal, A.C.O.; Kessler, B.M.; Knobeloch, K.P.; Van der Veen, A.G.
Qualification
Ph.D.
Degree granting institution
Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University, Leiden
hdl
1887/3308336
ISBN(s)
9789493289055