Regulation of the Drosophila Initiator Caspase Dronc through Ubiquitylation
Authors
Kamber Kaya, Hatem E.Faculty Advisor
Andreas BergmannAcademic Program
Cancer BiologyUMass Chan Affiliations
Molecular, Cell and Cancer Biology DepartmentDocument Type
Doctoral DissertationPublication Date
2017-01-17Keywords
ApoptosisUbiquitin
Drosophila
Dronc
Caspases
Cell Death
Post-Translational Modifications (PTMs)
Apoptosome
Biochemistry
Cell and Developmental Biology
Molecular Biology
Molecular Genetics
Metadata
Show full item recordAbstract
Apoptosis is a programmed cell death mechanism that is evolutionary conserved from worms to humans. Apoptosis is mediated by initiator and effector caspases. The initiator caspases carry long pro-domains for their interaction with scaffolding proteins to form a cell-death platform, which is essential for their activation. Activated initiator caspases then cleave effector caspases that execute cell death through cleaving downstream targets. In addition to their apoptotic function, caspases also participate in events where caspase activity is not required for cell killing, but for regulating other functions, so-called non-apoptotic functions of caspases. The Drosophila initiator caspase Dronc, the ortholog of mammalian caspase-2 and caspase-9 has a CARD domain that is essential for its interaction with the scaffolding protein Dark to form the apoptosome. Apoptosome formation is crucial for activation of Dronc. Activity of both initiator and effector caspases are further kept in control by the ubiquitin system to avoid inappropriate caspase activity. However, mechanistic details of how the ubiquitin system regulates activation of Dronc are not clear. Therefore, I investigated the ubiquitylation status of Dronc and its function in Drosophila. I found that Dronc is mono-ubiquitylated at Lys78 (K78) in its CARD domain, which blocks its interaction with Dark and formation of the apoptosome. Furthermore, I demonstrated that K78 mono-ubiquitylation plays an inhibitory role in Dronc’s non-apoptotic functions, which may not require its catalytic activity but may be important for the survival of the fly. This thesis study unveils the link between the ubiquitin system and caspases through a regulatory mechanism where a single mono-ubiquitylation event could inhibit both apoptotic and non-apoptotic functions of a caspase.DOI
10.13028/M2Z59ZPermanent Link to this Item
http://hdl.handle.net/20.500.14038/32262Rights
Copyright is held by the author, with all rights reserved.ae974a485f413a2113503eed53cd6c53
10.13028/M2Z59Z