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. Our study directly links autopalmitoylation to the transcriptional regulation of the Hippo pathway.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: PuiYee
authors.initials: P
authors.lastname: Chan
authors.affiliation: Key Laboratory for Molecular Enzymology &Engineering, Ministry of Education, School of Life Sciences, Jilin University, Changchun, China.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Baohui
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: DeRan
authors.affiliation: Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Molecular Biology &Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yu
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Gopala K
authors.initials: GK
authors.lastname: Jarugumilli
authors.affiliation: Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Molecular Biology &Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Deng
authors.affiliation: Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Molecular Biology &Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Duojia
authors.initials: D
authors.lastname: Pan
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Xuelian
authors.initials: X
authors.lastname: Luo
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Wu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D017124:Conserved Sequence; D003545:Cysteine / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000737:chemistry; D000090683:Hippo Signaling Pathway; D006801:Humans; D054878:Lipoylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010168:Palmitates / Q000737:chemistry; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D016415:Sequence Alignment; D015398:Signal Transduction; D000091262:TEA Domain Transcription Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D004268:DNA-Binding Proteins; C502521:Dis3 protein, Drosophila; D029721:Drosophila Proteins; D005231:Fatty Acids, Unsaturated; D009687:Nuclear Proteins; D010168:Palmitates; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; C101205:TEAD2 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C503814:Yki protein, Drosophila; C047007:15-hexadecynoic acid; D017346:Protein Serine-Threonine Kinases; D003545:Cysteine