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Title: Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway

Abstract

TEA domain (TEAD) transcription factors bind to the coactivators YAP and TAZ and regulate the transcriptional output of the Hippo pathway, playing critical roles in organ size control and tumorigenesis. Protein S-palmitoylation attaches a fatty acid, palmitate, to cysteine residues and regulates protein trafficking, membrane localization and signaling activities. Using activity-based chemical probes, we discovered that human TEADs possess intrinsic palmitoylating enzyme–like activities and undergo autopalmitoylation at evolutionarily conserved cysteine residues under physiological conditions. We determined the crystal structures of lipid-bound TEADs and found that the lipid chain of palmitate inserts into a conserved deep hydrophobic pocket. Strikingly, palmitoylation did not alter TEAD's localization, but it was required for TEAD's binding to YAP and TAZ and was dispensable for its binding to the Vgll4 tumor suppressor. Moreover, palmitoylation-deficient TEAD mutants impaired TAZ-mediated muscle differentiation in vitro and tissue overgrowth mediated by the Drosophila YAP homolog Yorkie in vivo. Furthermore, our study directly links autopalmitoylation to the transcriptional regulation of the Hippo pathway.

Authors:
 [1];  [2];  [1];  [1];  [3];  [1];  [3];  [3];  [4];  [1]
  1. Harvard Medical School, Charlestown, MA (United States)
  2. Jilin Univ., Changchun (China); Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
  3. Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)
  4. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE; American Cancer Society; U.S. National Inst. of Health/National Cancer Inst.; National Inst. of Health/National Inst. of Diabetes and Digestive and Kidney Diseases; National Inst. of Health/National Inst. of General Medical Sciences; National Inst. of Health/National Eye Inst.
OSTI Identifier:
1248393
Grant/Contract Number:  
AC02-06CH11357; 24929-RSG-13-291-01-TBE; R01CA181537; R01DK107651-01; R01GM107415; R01EY015708
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Chemical Biology
Additional Journal Information:
Journal Volume: 12; Journal Issue: 4; Journal ID: ISSN 1552-4450
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Cell signalling; Drosophilia; Post-translational modifications; X-ray crystallography

Citation Formats

Chan, PuiYee, Han, Xiao, Zheng, Baohui, DeRan, Michael, Yu, Jianzhong, Jarugumilli, Gopala K., Deng, Hua, Pan, Duojia, Luo, Xuelian, and Wu, Xu. Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway. United States: N. p., 2016. Web. doi:10.1038/nchembio.2036.
Chan, PuiYee, Han, Xiao, Zheng, Baohui, DeRan, Michael, Yu, Jianzhong, Jarugumilli, Gopala K., Deng, Hua, Pan, Duojia, Luo, Xuelian, & Wu, Xu. Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway. United States. https://doi.org/10.1038/nchembio.2036
Chan, PuiYee, Han, Xiao, Zheng, Baohui, DeRan, Michael, Yu, Jianzhong, Jarugumilli, Gopala K., Deng, Hua, Pan, Duojia, Luo, Xuelian, and Wu, Xu. 2016. "Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway". United States. https://doi.org/10.1038/nchembio.2036. https://www.osti.gov/servlets/purl/1248393.
@article{osti_1248393,
title = {Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway},
author = {Chan, PuiYee and Han, Xiao and Zheng, Baohui and DeRan, Michael and Yu, Jianzhong and Jarugumilli, Gopala K. and Deng, Hua and Pan, Duojia and Luo, Xuelian and Wu, Xu},
abstractNote = {TEA domain (TEAD) transcription factors bind to the coactivators YAP and TAZ and regulate the transcriptional output of the Hippo pathway, playing critical roles in organ size control and tumorigenesis. Protein S-palmitoylation attaches a fatty acid, palmitate, to cysteine residues and regulates protein trafficking, membrane localization and signaling activities. Using activity-based chemical probes, we discovered that human TEADs possess intrinsic palmitoylating enzyme–like activities and undergo autopalmitoylation at evolutionarily conserved cysteine residues under physiological conditions. We determined the crystal structures of lipid-bound TEADs and found that the lipid chain of palmitate inserts into a conserved deep hydrophobic pocket. Strikingly, palmitoylation did not alter TEAD's localization, but it was required for TEAD's binding to YAP and TAZ and was dispensable for its binding to the Vgll4 tumor suppressor. Moreover, palmitoylation-deficient TEAD mutants impaired TAZ-mediated muscle differentiation in vitro and tissue overgrowth mediated by the Drosophila YAP homolog Yorkie in vivo. Furthermore, our study directly links autopalmitoylation to the transcriptional regulation of the Hippo pathway.},
doi = {10.1038/nchembio.2036},
url = {https://www.osti.gov/biblio/1248393}, journal = {Nature Chemical Biology},
issn = {1552-4450},
number = 4,
volume = 12,
place = {United States},
year = {Mon Feb 22 00:00:00 EST 2016},
month = {Mon Feb 22 00:00:00 EST 2016}
}

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Works referenced in this record:

Hippo signaling in organ size control
journal, April 2007


Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo
journal, October 2011


Palmitoylome profiling reveals S-palmitoylation–dependent antiviral activity of IFITM3
journal, July 2010


Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy
journal, November 2015


2-Bromopalmitate Analogues as Activity-Based Probes To Explore Palmitoyl Acyltransferases
journal, May 2013


Exploring Protein Lipidation with Chemical Biology
journal, October 2011


Metabolic control of YAP and TAZ by the mevalonate pathway
journal, March 2014


Photoreceptor cGMP Phosphodiesterase δ Subunit (PDEδ) Functions as a Prenyl-binding Protein
journal, October 2003


Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis
journal, October 2007


The Hippo pathway and human cancer
journal, March 2013


Large-scale profiling of protein palmitoylation in mammalian cells
journal, January 2009


Protein palmitoylation in neuronal development and synaptic plasticity
journal, March 2010


The GDI-like solubilizing factor PDEδ sustains the spatial organization and signalling of Ras family proteins
journal, December 2011


Role of YAP/TAZ in mechanotransduction
journal, June 2011


Novel TAZ modulators enhance myogenic differentiation and muscle regeneration: Myogenic stimulation by novel TAZ modulators
journal, August 2014


Structural and functional analysis of the YAP-binding domain of human TEAD2
journal, April 2010


Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling
journal, April 1997


The Hippo Effector Yorkie Controls Normal Tissue Growth by Antagonizing Scalloped-Mediated Default Repression
journal, May 2013


Structural basis of YAP recognition by TEAD4 in the Hippo pathway
journal, February 2010


DHHC palmitoyl transferases: substrate interactions and (patho)physiology
journal, May 2011


Targeting Hippo pathway by specific interruption of YAP‐TEAD interaction using cyclic YAP‐like peptides
journal, November 2014


Unique self-palmitoylation activity of the transport protein particle component Bet3: A mechanism required for protein stability
journal, August 2006


Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP
journal, June 2012


Structural Basis for the Autoinhibition of c-Abl Tyrosine Kinase
journal, March 2003


Autoacylation of G Protein α Subunits
journal, September 1996


Small molecule inhibition of the KRAS–PDEδ interaction impairs oncogenic KRAS signalling
journal, May 2013


The Hippo Signaling Pathway in Development and Cancer
journal, October 2010


Palmitoylation of Intracellular Signaling Proteins: Regulation and Function
journal, June 2004


Structural insights into the YAP and TEAD complex
journal, February 2010


The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment
journal, December 2013


Palmitoylated proteins: purification and identification
journal, June 2007


Trafficking and signaling by fatty-acylated and prenylated proteins
journal, October 2006


Structure of palmitoylated BET3: insights into TRAPP complex assembly and membrane localization
journal, February 2005


A Peptide Mimicking VGLL4 Function Acts as a YAP Antagonist Therapy against Gastric Cancer
journal, February 2014


TEAD mediates YAP-dependent gene induction and growth control
journal, July 2008


Clickable Analogue of Cerulenin as Chemical Probe to Explore Protein Palmitoylation
journal, October 2014


Global Analysis of Protein Palmitoylation in Yeast
journal, June 2006


Palmitoylation of TEAD Transcription Factors Is Required for Their Stability and Function in Hippo Pathway Signaling
journal, January 2016


A Peptide Mimicking VGLL4 Function Acts as a YAP Antagonist Therapy against Gastric Cancer
journal, March 2014


Global Analysis of Protein Palmitoylation in Yeast
journal, June 2006


Yorkie and Scalloped: Partners in Growth Activation
journal, March 2008


The Hippo Signaling Pathway in Development and Cancer
journal, October 2010


The Hippo Effector Yorkie Controls Normal Tissue Growth by Antagonizing Scalloped-Mediated Default Repression
journal, May 2013


Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy
journal, November 2015


Structural Basis for Latency and Function of Immune Inhibitor A Metallopeptidase, a Modulator of the Bacillus anthracis Secretome
journal, January 2016


DHHC palmitoyl transferases: substrate interactions and (patho)physiology
journal, May 2011


A Myristoyl/Phosphotyrosine Switch Regulates c-Abl
journal, March 2003


Variation on an Src-like Theme
journal, March 2003


Clickable Analogue of Cerulenin as Chemical Probe to Explore Protein Palmitoylation
journal, October 2014


Exploring Protein Lipidation with Chemical Biology
journal, October 2011


Role of YAP/TAZ in mechanotransduction
journal, June 2011


Palmitoylome profiling reveals S-palmitoylation–dependent antiviral activity of IFITM3
journal, July 2010


Trafficking and signaling by fatty-acylated and prenylated proteins
journal, October 2006


Large-scale profiling of protein palmitoylation in mammalian cells
journal, January 2009


Palmitoylated proteins: purification and identification
journal, June 2007


Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis
journal, October 2007


The Hippo pathway and human cancer
journal, March 2013


The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment
journal, December 2013


Protein palmitoylation in neuronal development and synaptic plasticity
journal, March 2010


Structure of palmitoylated BET3: insights into TRAPP complex assembly and membrane localization
journal, February 2005


Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling
journal, April 1997


DHHC Protein S -Acyltransferases Use Similar Ping-Pong Kinetic Mechanisms but Display Different Acyl-CoA Specificities
journal, January 2012


Hippo signaling in organ size control
journal, April 2007


TEAD mediates YAP-dependent gene induction and growth control
journal, July 2008


Structural basis of YAP recognition by TEAD4 in the Hippo pathway
journal, February 2010


Palmitoylation of Intracellular Signaling Proteins: Regulation and Function
journal, June 2004


Works referencing / citing this record:

Regulation of the Hippo pathway in cancer biology
journal, March 2018


ZDHHC7-mediated S-palmitoylation of Scribble regulates cell polarity
journal, July 2016


A fluorescent probe for cysteine depalmitoylation reveals dynamic APT signaling
journal, December 2016


Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes
journal, January 2018


ABHD10 is an S-depalmitoylase affecting redox homeostasis through peroxiredoxin-5
journal, November 2019


Structural and ligand-binding analysis of the YAP-binding domain of transcription factor TEAD4
journal, June 2018


Structure and function of DHHC protein S-acyltransferases
journal, June 2017


The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics
journal, July 2018


Hippo pathway inhibition by blocking the YAP/TAZ–TEAD interface: a patent review
journal, November 2018


Protein Palmitoylation and Its Role in Bacterial and Viral Infections
journal, January 2018


Repurposing of Drugs Targeting YAP-TEAD Functions
journal, September 2018


GPCR-Hippo Signaling in Cancer
journal, May 2019


Nutrient-Dependent Changes of Protein Palmitoylation: Impact on Nuclear Enzymes and Regulation of Gene Expression
journal, November 2018


Diverse Functions of Lipids and Lipid Metabolism in Development
journal, December 2019


DNA-binding mechanism of the Hippo pathway transcription factor TEAD4
journal, April 2017


Mediated nuclear import and export of TAZ and the underlying molecular requirements
journal, November 2018


Auto-fatty acylation of transcription factor RFX3 regulates ciliogenesis
journal, August 2018


Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth
posted_content, April 2018


The role of YAP/TAZ activity in cancer metabolic reprogramming
journal, September 2018


Protein palmitoylation and cancer
journal, September 2018


Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors
journal, March 2018


The Roles of YAP/TAZ and the Hippo Pathway in Healthy and Diseased Skin
journal, May 2019


Regulation of TEAD Transcription Factors in Cancer Biology
journal, June 2019


A fluorescent probe for cysteine depalmitoylation reveals dynamic APT signaling
journal, December 2016


Active and dynamic mitochondrial S-depalmitoylation revealed by targeted fluorescent probes
journal, January 2018


Crystal structure of TAZ-TEAD complex reveals a distinct interaction mode from that of YAP-TEAD complex
journal, May 2017


The role of YAP/TAZ activity in cancer metabolic reprogramming
journal, September 2018


Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches
journal, June 2017


Protein Palmitoylation and Its Role in Bacterial and Viral Infections
journal, January 2018


Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors
journal, March 2018


Repurposing of Drugs Targeting YAP-TEAD Functions
journal, September 2018


GPCR-Hippo Signaling in Cancer
journal, May 2019


Regulation of TEAD Transcription Factors in Cancer Biology
journal, June 2019


A combat with the YAP/TAZ-TEAD oncoproteins for cancer therapy
journal, January 2020