Overview - Systems perspective on protein ubiquitination
Ubiquitin proteasome system (UPS) in the oxidative stress response
Oxidative stress is one of the most prevalent types of environmental stresses and underlies the development and progression of many diseases. In response to oxidative stress, the UPS regulates a multitude of cellular processes, from protein degradation to the control of protein synthesis. Our lab investigates how the distinct roles played by ubiquitin control gene expression, protein dynamics, and ultimately cellular resistance to stress. We have a particular interest in understanding how K63 ubiquitin, a unique type of ubiquitin chain, modifies ribosomes and controls translation in response to oxidative stress. Our lab uses an array of cellular and molecular biology tools, protein biochemistry, proteomics, structural biology, and next generation sequencing to tackle these questions.
Cracking the Ubiquitin Code
The ubiquitination system acts through a cascade of enzymes that post-translationally controls most of cellular functions. Yeast encodes in its genome ~120 genes for ubiquitin enzymes and researchers estimate that humans might encode ~ 1000, which could represent up to 5% of the entire human genome. However, many of the targets modified by ubiquitin, the enzymes responsible for their modification, their modes of regulation, and the type of ubiquitin chain that can be assembled remains to be understood. To resolve this ubiquitination code, our lab is investing in a variety of genome-wide methods, genome editing tools, proteomics, and computational approaches to understand the evolutionary conservation of these pathways and the underlying principles of this regulatory modification. Our ultimate goal is to dissect these unique pathways, characterize their functional regulators, and develop tools to manipulate cellular physiology to support cellular health.
courtesy of A. Maduka
Redox role of ubiquitin in human cells
Oxidative stress, impairment of proteasomal degradation, accumulation of ubiquitinated proteins, and deregulation of proteostasis are hallmarks of neurodegenerative diseases such as Parkinson’s and Alzheimer’s. With the increase of the life expectancy in humans, these diseases became highly prevalent, however very limited resources are available for diagnosis and proper treatment. Understanding the roles of the ubiquitin proteasome system in human cells could provide a pathway to develop new therapies. We are investigating the role of the ubiquitin system in human cells during oxidative stress. Our ultimate goal is to develop ubiquitin-based therapies to increase cellular resistance to stress-related diseases or reduce cellular viability to target cancer cells.
Our research is supported by:
PI: National Institute of General Medical Sciences (NIGMS) R35 MIRA award - R35GM137954
Dissecting the roles of ubiquitin in translation control
PI: National Institute of Environmental Health Sciences (NIEHS) K99/R00 award - R00ES025835
Defining the roles of ubiquitination during the environmental stress response
National Institute of Allergy and Infectious Disease (NIAID) R01 award - R01AI155512
Regulation of RIG-I signaling and viral immune evasion by ufmylation (PI: Stacy Horner, co-PI: Gustavo Silva)