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Smad7 palmitoylation by the S-acyltransferase zDHHC17 enhances its inhibitory effect on TGF-ß/Smad signaling.
Voytyuk, Oleksandr; Ohata, Yae; Moustakas, Aristidis; Ten Dijke, Peter; Heldin, Carl-Henrik.
Afiliación
  • Voytyuk O; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, Uppsala, Sweden. Electronic address: Oleksandr.voytyuk@imbim.uu.se.
  • Ohata Y; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, Uppsala, Sweden.
  • Moustakas A; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, Uppsala, Sweden.
  • Ten Dijke P; Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.
  • Heldin CH; Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, Uppsala, Sweden.
J Biol Chem ; 300(7): 107462, 2024 Jul.
Article en En | MEDLINE | ID: mdl-38876303
ABSTRACT
Intracellular signaling by the pleiotropic cytokine transforming growth factor-ß (TGF-ß) is inhibited by Smad7 in a feedback control mechanism. The activity of Smad7 is tightly regulated by multiple post-translational modifications. Using resin-assisted capture and metabolic labeling methods, we show here that Smad7 is S-palmitoylated in mammary epithelial cell models that are widely studied because of their strong responses to TGF-ß and their biological relevance to mammary development and tumor progression. S-palmitoylation of Smad7 is mediated by zDHHC17, a member of a family of 23 S-acyltransferase enzymes. Moreover, we identified four cysteine residues (Cys202, Cys225, Cys415, and Cys417) in Smad7 as palmitoylation acceptor sites. S-palmitoylation of Smad7 on Cys415 and Cys417 promoted the translocation of Smad7 from the nucleus to the cytoplasm, enhanced the stability of the Smad7 protein, and enforced its inhibitory effect on TGF-ß-induced Smad transcriptional response. Thus, our findings reveal a new post-translational modification of Smad7, and highlight an important role of S-palmitoylation to enhance inhibition of TGF-ß/Smad signaling by Smad7.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Aciltransferasas / Transducción de Señal / Factor de Crecimiento Transformador beta / Proteína smad7 / Lipoilación Límite: Animals / Humans Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Aciltransferasas / Transducción de Señal / Factor de Crecimiento Transformador beta / Proteína smad7 / Lipoilación Límite: Animals / Humans Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos