This thesis examines the evidence for regulatory ubiquitination by focusing on A20. It provides
an insightful and in-depth evaluation of the current literature by critically examining the
evidence of K63-linked regulatory ubiquitination in regulating cell-signalling. It is also the
first thesis to directly test the role of regulatory ubiquitination in NF-kB signaling in vivo.
The case for regulatory ubiquitination has been to a large extent predicated upon the presumed
deubiquitinase activity of A20 long considered a key regulator of inflammatory responses as
mice lacking A20 die from multi-organ inflammation and cachexia. The theses reports the
creation and characterization of a knock-in mouse that expresses a mutated form of A20 which
selectively lacks the deubiquitinase activity. The knock-in mice surprisingly display
completely normal NF- B activation with no accompanying inflammatory phenotype. Given that the
presumed role of A20 as a deubiquitinase has been used to supportthe importance of regulatory
K63-linked ubiquitination in NF-kB signaling this study will help focus future research
efforts into alternative target pathways that do not depend on K63 ubiquitination. In fact the
work suggests that it might be important to revisit the role of K63-linked polyubiquitination
in cell-signalling. Ubiquitin Chains: Degradation and Beyond is essential reading for anyone
conducting research in cell-signalling and immunology.Dr. Arnab De received his PhD from the
Department of Microbiology & Immunology at Columbia University. During his PhD he developed
transgenic mice to study the mechanism of action of a critical tumor-suppressor called A20. He
is also well known for having developed peptide-based prodrugs as therapeutics for diabetes.
His work has been reported by the media and has resulted in multiple patents and publications
in peer reviewed journals. He presented his findings at the American Peptide Symposium and was
awarded the Young Investigator's Award. He is the author of the book entitled Application of
Peptide-Based Prodrug Chemistry in Drug Development with a foreword written by Professor Jean
Martinez (Former President European Peptide Society) and published in the series
SpringerBriefs in Pharmaceutical Science & Drug Development. His research interests lie at the
intersection of chemistry and medicine. Besides biomedical research he is also generally
interested in public health policy and general scientific outreach.
