A non-nucleotide agonist that binds covalently to cysteine residues of STING
Stimulator of interferon genes (STING) is an ER-localized transmembrane protein and the receptor for 2',3'-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), which is a second messenger produced by cGAMP synthase (cGAS), a cytosolic double-stranded DNA sensor. The cGAS...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Japan Society for Cell Biology
2022-12-01
|
| Series: | Cell Structure and Function |
| Subjects: | |
| Online Access: | https://www.jstage.jst.go.jp/article/csf/48/1/48_22085/_html/-char/en |
| _version_ | 1827825972673511424 |
|---|---|
| author | Kentaro Matsumoto Shenwei Ni Hiroyuki Arai Takashi Toyama Yoshiro Saito Takehiro Suzuki Naoshi Dohmae Kojiro Mukai Tomohiko Taguchi |
| author_facet | Kentaro Matsumoto Shenwei Ni Hiroyuki Arai Takashi Toyama Yoshiro Saito Takehiro Suzuki Naoshi Dohmae Kojiro Mukai Tomohiko Taguchi |
| author_sort | Kentaro Matsumoto |
| collection | DOAJ |
| description | Stimulator of interferon genes (STING) is an ER-localized transmembrane protein and the receptor for 2',3'-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), which is a second messenger produced by cGAMP synthase (cGAS), a cytosolic double-stranded DNA sensor. The cGAS-STING pathway plays a critical role in the innate immune response to infection of a variety of DNA pathogens through the induction of the type I interferons. Pharmacological activation of STING is a promising therapeutic strategy for cancer, thus the development of potent and selective STING agonists has been pursued. Here we report that mouse STING can be activated by phenylarsine oxide (PAO), a membrane permeable trivalent arsenic compound that preferentially reacts with thiol group of cysteine residue (Cys). The activation of STING with PAO does not require cGAS or cGAMP. Mass spectrometric analysis of the peptides generated by trypsin and chymotrypsin digestion of STING identifies several PAO adducts, suggesting that PAO covalently binds to STING. Screening of STING variants with single Cys to serine residues (Ser) reveals that Cys88 and Cys291 are critical to the response to PAO. STING activation with PAO, as with cGAMP, requires the ER-to-Golgi traffic and palmitoylation of STING. Our results identify a non-nucleotide STING agonist that does not target the cGAMP-binding pocket, and demonstrate that Cys of STING can be a novel target for the development of STING agonist. Key words: STING agonist, cysteine modification, innate immunity, phenylarsine oxide |
| first_indexed | 2024-03-12T02:57:46Z |
| format | Article |
| id | doaj.art-107fff2f745949abad01f44bf228cfb1 |
| institution | Directory Open Access Journal |
| issn | 0386-7196 1347-3700 |
| language | English |
| last_indexed | 2024-03-12T02:57:46Z |
| publishDate | 2022-12-01 |
| publisher | Japan Society for Cell Biology |
| record_format | Article |
| series | Cell Structure and Function |
| spelling | doaj.art-107fff2f745949abad01f44bf228cfb12023-09-03T15:05:51ZengJapan Society for Cell BiologyCell Structure and Function0386-71961347-37002022-12-01481597010.1247/csf.22085csfA non-nucleotide agonist that binds covalently to cysteine residues of STINGKentaro Matsumoto0Shenwei Ni1Hiroyuki Arai2Takashi Toyama3Yoshiro Saito4Takehiro Suzuki5Naoshi Dohmae6Kojiro Mukai7Tomohiko Taguchi8Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku UniversityDepartment of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of TokyoDepartment of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of TokyoLaboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku UniversityLaboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku UniversityBiomolecular Characterization Unit, Technology Platform Division, RIKEN Center for Sustainable Resource ScienceBiomolecular Characterization Unit, Technology Platform Division, RIKEN Center for Sustainable Resource ScienceLaboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku UniversityLaboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku UniversityStimulator of interferon genes (STING) is an ER-localized transmembrane protein and the receptor for 2',3'-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), which is a second messenger produced by cGAMP synthase (cGAS), a cytosolic double-stranded DNA sensor. The cGAS-STING pathway plays a critical role in the innate immune response to infection of a variety of DNA pathogens through the induction of the type I interferons. Pharmacological activation of STING is a promising therapeutic strategy for cancer, thus the development of potent and selective STING agonists has been pursued. Here we report that mouse STING can be activated by phenylarsine oxide (PAO), a membrane permeable trivalent arsenic compound that preferentially reacts with thiol group of cysteine residue (Cys). The activation of STING with PAO does not require cGAS or cGAMP. Mass spectrometric analysis of the peptides generated by trypsin and chymotrypsin digestion of STING identifies several PAO adducts, suggesting that PAO covalently binds to STING. Screening of STING variants with single Cys to serine residues (Ser) reveals that Cys88 and Cys291 are critical to the response to PAO. STING activation with PAO, as with cGAMP, requires the ER-to-Golgi traffic and palmitoylation of STING. Our results identify a non-nucleotide STING agonist that does not target the cGAMP-binding pocket, and demonstrate that Cys of STING can be a novel target for the development of STING agonist. Key words: STING agonist, cysteine modification, innate immunity, phenylarsine oxidehttps://www.jstage.jst.go.jp/article/csf/48/1/48_22085/_html/-char/ensting agonistcysteine modificationinnate immunityphenylarsine oxide |
| spellingShingle | Kentaro Matsumoto Shenwei Ni Hiroyuki Arai Takashi Toyama Yoshiro Saito Takehiro Suzuki Naoshi Dohmae Kojiro Mukai Tomohiko Taguchi A non-nucleotide agonist that binds covalently to cysteine residues of STING Cell Structure and Function sting agonist cysteine modification innate immunity phenylarsine oxide |
| title | A non-nucleotide agonist that binds covalently to cysteine residues of STING |
| title_full | A non-nucleotide agonist that binds covalently to cysteine residues of STING |
| title_fullStr | A non-nucleotide agonist that binds covalently to cysteine residues of STING |
| title_full_unstemmed | A non-nucleotide agonist that binds covalently to cysteine residues of STING |
| title_short | A non-nucleotide agonist that binds covalently to cysteine residues of STING |
| title_sort | non nucleotide agonist that binds covalently to cysteine residues of sting |
| topic | sting agonist cysteine modification innate immunity phenylarsine oxide |
| url | https://www.jstage.jst.go.jp/article/csf/48/1/48_22085/_html/-char/en |
| work_keys_str_mv | AT kentaromatsumoto anonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT shenweini anonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT hiroyukiarai anonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT takashitoyama anonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT yoshirosaito anonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT takehirosuzuki anonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT naoshidohmae anonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT kojiromukai anonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT tomohikotaguchi anonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT kentaromatsumoto nonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT shenweini nonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT hiroyukiarai nonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT takashitoyama nonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT yoshirosaito nonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT takehirosuzuki nonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT naoshidohmae nonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT kojiromukai nonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting AT tomohikotaguchi nonnucleotideagonistthatbindscovalentlytocysteineresiduesofsting |