BASIC RESEARCH

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Basic Research

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Protein ubiquitination and degradation

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My lab focuses on identifying and studying molecular pathways that modulate the inflammatory cascade and innate immunity (1), mitochondria function/mitophagy (2), and DAMPs/inflammasome/necroptosis (3) in order to develop novel therapeutics for various diseases.

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Protein ubiquitination pathway

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Here at the Aging institute, we are also interested in studying the various aging processes such as lysosomal dysfunction, autophagy/mitophagy, SASP, Senescence, etc. We seek to identify therapeutic targets that regulate these processes within the context of a unifying control mechanism which could provide new opportunities for translation of basic observations to pre-clinical models, and ultimately therapeutics for human diseases.

Specifically, we have been studying the role of protein ubiquitination for many years, and have made several important discoveries that connect E3 ligases to their target proteins and biological activities. Protein ubiquitination is the major protein processing pathways in cells by which ubiquitin (Ub) flags a targeted protein for degradation through the 26s proteasome or lysosome. Protein ubiquitination has been implicated in many diseases, and there has been an increasing interest in investigating the role of protein ubiquitination in inflammatory conditions. There are now several FDA approved compounds, including proteasome inhibitors that target the downstream components of this pathway. However, majority of the >800 upstream E3 ligases remains poorly characterized. Thus we investigate how and which protein ubiquitination processes impact the above areas.

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Approach

There are two approaches we use to determine the E3 ligases for the specific substrate. Prior to 2016, our method was based on overexpressing a homemade E3 ligase library (>250 E3 ligase plasmids) in cells, followed by substrate protein immunoblotting (WB). However, it is labor intensive to transfect cells with hundreds of individual plasmids and performs WB analysis for the substrate of interest. Recently we have set up a robotic-based HTS system (HTS1-1.jpg), which has the ability to handle nano-liter volumes of liquid in 384 wells. Using this platform, we have developed an E3 ligase siRNA library (>850 genes) covers pretty much all the authentic and predicted E3 ligases, and we have been able to conduct an unbiased screen to identify every potential E3 ligase via phenotypic assays. The phenotypic assays involve measuring cytokines through ELISA, fluorescent intensity of labeled substrates, sub-cellular substrate localization, and others. Alternatively, we also use proteomics to identify the unknown E3 ligase as complimentary approach.

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