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A novel gain-of-function phosphorylation site modulates PTPN22 inhibition of TCR signaling.
Zhuang, Chuling; Yang, Shen; Gonzalez, Carlos G; Ainsworth, Richard I; Li, Sheng; Kobayashi, Masumi Takayama; Wierzbicki, Igor; Rossitto, Leigh-Ana M; Wen, Yutao; Peti, Wolfgang; Stanford, Stephanie M; Gonzalez, David J; Murali, Ramachandran; Santelli, Eugenio; Bottini, Nunzio.
  • Zhuang C; Department of Medicine, Altman Clinical and Translational Research Institute, University of California, San Diego, California, USA.
  • Yang S; Department of Medicine, Altman Clinical and Translational Research Institute, University of California, San Diego, California, USA; Department of Medicine, Kao Autoimmunity Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Gonzalez CG; Department of Pharmacology, University of California, San Diego, California, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, California, USA.
  • Ainsworth RI; Department of Medicine, Kao Autoimmunity Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Li S; Department of Medicine, University of California, San Diego, California, USA.
  • Kobayashi MT; Department of Molecular Biology and Biophysics, University of Connecticut Health, Farmington, Connecticut, USA.
  • Wierzbicki I; Department of Pharmacology, University of California, San Diego, California, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, California, USA.
  • Rossitto LM; Department of Pharmacology, University of California, San Diego, California, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, California, USA.
  • Wen Y; Department of Medicine, Altman Clinical and Translational Research Institute, University of California, San Diego, California, USA.
  • Peti W; Department of Molecular Biology and Biophysics, University of Connecticut Health, Farmington, Connecticut, USA.
  • Stanford SM; Department of Medicine, Altman Clinical and Translational Research Institute, University of California, San Diego, California, USA.
  • Gonzalez DJ; Department of Pharmacology, University of California, San Diego, California, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, California, USA.
  • Murali R; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Santelli E; Department of Medicine, Altman Clinical and Translational Research Institute, University of California, San Diego, California, USA; Department of Medicine, Kao Autoimmunity Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Bottini N; Department of Medicine, Altman Clinical and Translational Research Institute, University of California, San Diego, California, USA; Department of Medicine, Kao Autoimmunity Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. Electronic address: Nunzio.Bottini@cshs.org.
J Biol Chem ; 300(6): 107393, 2024 Jun.
Article en En | MEDLINE | ID: mdl-38777143
ABSTRACT
Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is encoded by a major autoimmunity gene and is a known inhibitor of T cell receptor (TCR) signaling and drug target for cancer immunotherapy. However, little is known about PTPN22 posttranslational regulation. Here, we characterize a phosphorylation site at Ser325 situated C terminal to the catalytic domain of PTPN22 and its roles in altering protein function. In human T cells, Ser325 is phosphorylated by glycogen synthase kinase-3 (GSK3) following TCR stimulation, which promotes its TCR-inhibitory activity. Signaling through the major TCR-dependent pathway under PTPN22 control was enhanced by CRISPR/Cas9-mediated suppression of Ser325 phosphorylation and inhibited by mimicking it via glutamic acid substitution. Global phospho-mass spectrometry showed Ser325 phosphorylation state alters downstream transcriptional activity through enrichment of Swi3p, Rsc8p, and Moira domain binding proteins, and next-generation sequencing revealed it differentially regulates the expression of chemokines and T cell activation pathways. Moreover, in vitro kinetic data suggest the modulation of activity depends on a cellular context. Finally, we begin to address the structural and mechanistic basis for the influence of Ser325 phosphorylation on the protein's properties by deuterium exchange mass spectrometry and NMR spectroscopy. In conclusion, this study explores the function of a novel phosphorylation site of PTPN22 that is involved in complex regulation of TCR signaling and provides details that might inform the future development of allosteric modulators of PTPN22.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Receptores de Antígenos de Linfocitos T / Transducción de Señal / Proteína Tirosina Fosfatasa no Receptora Tipo 22 Límite: Humans Idioma: En Año: 2024 Tipo del documento: Article
Texto completo
Imprimir
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PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Receptores de Antígenos de Linfocitos T / Transducción de Señal / Proteína Tirosina Fosfatasa no Receptora Tipo 22 Límite: Humans Idioma: En Año: 2024 Tipo del documento: Article