Proteasome and VCP inhibition blocks necroptosis in HT-29 cells
is a programmed form of cell death mediated by the formation of a detergent-insoluble
protein complex called necrosome. Receptor Interacting Protein Kinases (RIPK) 1 and 3
have been identified as the key components of the necrosome. Phosphorylation and
ubiquitination of several RIPK1/3 residues have been implicated to play important roles
in regulating apoptosis and ... read morenecroptosis. As the main mechanism for cellular protein
degradation, ubiquitin-proteasome system (UPS) has been associated with a myriad of
cellular pathways, including apoptosis. However, the mechanism and function of UPS under
apoptotic or necroptotic conditions are poorly understood. Here we report that
proteasome inhibitor bortezomib and Valosin-Containing Protein (VCP) inhibitor NMS-873
inhibit necroptosis in human colorectal cancer HT-29 cells. VCP inhibition clearly
changes the ubiquitination profile of RIPK1 and RIPK3 in the necrosome. RIPK1 interacts
with VCP upon TNFɑ stimulation in a complex separate from the necrosome or TNF
Receptor 1 signaling complex.
Thesis (M.S.)--Tufts University, 2018.
Submitted to the Dept. of Pharmacology and Drug Development.
Advisor: Alexei Degterev.
Keyword: Pharmacology.read less