Protein S-palmitoylation is a dynamic post-translational modification attaching the 16-carbon fatty acid (palmitate) to the cysteine residues. Genetic studies have shown that 23 of DHHC (Asp-His-His-Cys) domain-containing enzymes are protein palmitoyl acyltransferases (PATs). In addition, some proteins could undergo non-enzymatic autopalmitoylation when bound to palmitoyl-Coenzyme A (CoA) directly. To explore their functions, we have developed novel activity-based chemical probes to covalently label and profile PATs and autopalmitoylated proteins in cells. Through proteomic, biochemical and structural studies, we have discovered that the mammalian TEA domain family (TEAD/TEF) transcription factors (TEAD1-4) are autopalmitoylated proteins. TEADs are essential transcription factors that bind to the transcription co-activators YAP/TAZ and regulate Hippo pathway transcriptional output. Deregulation of TEAD-YAP complex has been linked to defective regeneration and organ size control in liver, skin, colon, and heart. Therefore, understanding this novel regulation will shed light on how fatty acid metabolism and autopalmitoylation regulate transcription factors.
Our specific aims of this proposal include: (1) To determine the regulatory mechanism(s) of TEADs autopalmitoylation. (2) To investigate the roles of TEAD palmitoylation in regulating Hippo pathway in vitro and in vivo. (3) To develop small molecule inhibitors of TEAD autopalmitoylation as chemical tools.

Public Health Relevance

TEA domain family (TEAD/TEF) proteins (TEAD1-4) are essential transcription factors regulating Hippo pathway transcriptional output, and their dysfunction is linked to defective regeneration and organ size control in liver, skin, colon, and heart. We discovered that TEADs are autopalmitoylated proteins and palmitoylation is essential for their functions. Understanding this novel signaling mechanism will provide new insights into how fatty acid metabolism and palmitoylation regulate transcription, and discover potential therapeutic agents for human diseases resulting from dysfunctional Hippo signaling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK107651-04
Application #
9610644
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Maruvada, Padma
Project Start
2015-12-01
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
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