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S-lactoyl modification of KEAP1 by a reactive glycolytic metabolite activates NRF2 signaling
KEAP1 (Kelch-like ECH-associated protein), a cytoplasmic repressor of the oxidative stress responsive transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2), senses the presence of electrophilic agents by modification of its sensor cysteine residues. In addition to xenobiotics, seve...
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| Published in: | Proceedings of the National Academy of Sciences - PNAS 2023-05, Vol.120 (20), p.e2300763120-e2300763120 |
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| container_end_page | e2300763120 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 120 |
| creator | Ko, Yeonjin Hong, Mannkyu Lee, Seungbeom Kumar, Manoj Ibrahim, Lara Nutsch, Kayla Stanton, Caroline Sondermann, Phillip Sandoval, Braddock Bulos, Maya L Iaconelli, Jonathan Chatterjee, Arnab K Wiseman, R Luke Schultz, Peter G Bollong, Michael J |
| description | KEAP1 (Kelch-like ECH-associated protein), a cytoplasmic repressor of the oxidative stress responsive transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2), senses the presence of electrophilic agents by modification of its sensor cysteine residues. In addition to xenobiotics, several reactive metabolites have been shown to covalently modify key cysteines on KEAP1, although the full repertoire of these molecules and their respective modifications remain undefined. Here, we report the discovery of sAKZ692, a small molecule identified by high-throughput screening that stimulates NRF2 transcriptional activity in cells by inhibiting the glycolytic enzyme pyruvate kinase. sAKZ692 treatment promotes the buildup of glyceraldehyde 3-phosphate, a metabolite which leads to S-lactate modification of cysteine sensor residues of KEAP1, resulting in NRF2-dependent transcription. This work identifies a posttranslational modification of cysteine derived from a reactive central carbon metabolite and helps further define the complex relationship between metabolism and the oxidative stress-sensing machinery of the cell. |
| doi_str_mv | 10.1073/pnas.2300763120 |
| format | article |
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In addition to xenobiotics, several reactive metabolites have been shown to covalently modify key cysteines on KEAP1, although the full repertoire of these molecules and their respective modifications remain undefined. Here, we report the discovery of sAKZ692, a small molecule identified by high-throughput screening that stimulates NRF2 transcriptional activity in cells by inhibiting the glycolytic enzyme pyruvate kinase. sAKZ692 treatment promotes the buildup of glyceraldehyde 3-phosphate, a metabolite which leads to S-lactate modification of cysteine sensor residues of KEAP1, resulting in NRF2-dependent transcription. This work identifies a posttranslational modification of cysteine derived from a reactive central carbon metabolite and helps further define the complex relationship between metabolism and the oxidative stress-sensing machinery of the cell.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2300763120</identifier><identifier>PMID: 37155889</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Biological Sciences ; Cysteine ; Cysteine - metabolism ; Glyceraldehyde ; Glyceraldehyde 3-phosphate ; Glycolysis ; High-throughput screening ; Kelch-Like ECH-Associated Protein 1 - chemistry ; Metabolites ; NF-E2-Related Factor 2 - metabolism ; Oxidative metabolism ; Oxidative Stress ; Pyruvate kinase ; Pyruvic acid ; Reagents ; Residues ; Signal Transduction ; Xenobiotics</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2023-05, Vol.120 (20), p.e2300763120-e2300763120</ispartof><rights>Copyright National Academy of Sciences May 16, 2023</rights><rights>Copyright © 2023 the Author(s). Published by PNAS. 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-338ede898562010505160b9a81f6a6c25105c98e1e75831d5cda030b26ba17a3</citedby><cites>FETCH-LOGICAL-c422t-338ede898562010505160b9a81f6a6c25105c98e1e75831d5cda030b26ba17a3</cites><orcidid>0000-0001-9287-6840 ; 0000-0003-3188-1202 ; 0000-0001-9439-1476 ; 0000-0001-5171-7982</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193962/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193962/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37155889$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ko, Yeonjin</creatorcontrib><creatorcontrib>Hong, Mannkyu</creatorcontrib><creatorcontrib>Lee, Seungbeom</creatorcontrib><creatorcontrib>Kumar, Manoj</creatorcontrib><creatorcontrib>Ibrahim, Lara</creatorcontrib><creatorcontrib>Nutsch, Kayla</creatorcontrib><creatorcontrib>Stanton, Caroline</creatorcontrib><creatorcontrib>Sondermann, Phillip</creatorcontrib><creatorcontrib>Sandoval, Braddock</creatorcontrib><creatorcontrib>Bulos, Maya L</creatorcontrib><creatorcontrib>Iaconelli, Jonathan</creatorcontrib><creatorcontrib>Chatterjee, Arnab K</creatorcontrib><creatorcontrib>Wiseman, R Luke</creatorcontrib><creatorcontrib>Schultz, Peter G</creatorcontrib><creatorcontrib>Bollong, Michael J</creatorcontrib><title>S-lactoyl modification of KEAP1 by a reactive glycolytic metabolite activates NRF2 signaling</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>KEAP1 (Kelch-like ECH-associated protein), a cytoplasmic repressor of the oxidative stress responsive transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2), senses the presence of electrophilic agents by modification of its sensor cysteine residues. 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This work identifies a posttranslational modification of cysteine derived from a reactive central carbon metabolite and helps further define the complex relationship between metabolism and the oxidative stress-sensing machinery of the cell.</description><subject>Biological Sciences</subject><subject>Cysteine</subject><subject>Cysteine - metabolism</subject><subject>Glyceraldehyde</subject><subject>Glyceraldehyde 3-phosphate</subject><subject>Glycolysis</subject><subject>High-throughput screening</subject><subject>Kelch-Like ECH-Associated Protein 1 - chemistry</subject><subject>Metabolites</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Oxidative metabolism</subject><subject>Oxidative Stress</subject><subject>Pyruvate kinase</subject><subject>Pyruvic acid</subject><subject>Reagents</subject><subject>Residues</subject><subject>Signal Transduction</subject><subject>Xenobiotics</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNpdkc1rFTEUxYNY2md17U4CbtxMe28yySQrKaVVsbSldimETCbzTMlMnpO8wvz3Tj-tri7c87uHeziEvEc4QGj44Wa0-YBxgEZyZPCKrBA0VrLW8JqsAFhTqZrVe-RNzjcAoIWCXbLHGxRCKb0iP39U0bqS5kiH1IU-OFtCGmnq6feTo0uk7UwtnfzChFtP13F2Kc4lODr4YtsUQ_H0XrTFZ3p-dcpoDuvRxjCu35Kd3sbs3z3OfXJ9enJ9_LU6u_jy7fjorHI1Y6XiXPnOK62EZIAgQKCEVluFvbTSMbHsnFYefSMUx064zgKHlsnWYmP5Pvn8YLvZtoPvnB_LZKPZTGGw02ySDeZfZQy_zDrdGgTUXEu2OHx6dJjS763PxQwhOx-jHX3aZsMUopBa1XxBP_6H3qTttOS9pyRyDlws1OED5aaU8-T7528QzF1z5q4587e55eLDyxDP_FNV_A_jUpPv</recordid><startdate>20230516</startdate><enddate>20230516</enddate><creator>Ko, Yeonjin</creator><creator>Hong, Mannkyu</creator><creator>Lee, Seungbeom</creator><creator>Kumar, Manoj</creator><creator>Ibrahim, Lara</creator><creator>Nutsch, Kayla</creator><creator>Stanton, Caroline</creator><creator>Sondermann, Phillip</creator><creator>Sandoval, Braddock</creator><creator>Bulos, Maya L</creator><creator>Iaconelli, Jonathan</creator><creator>Chatterjee, Arnab K</creator><creator>Wiseman, R Luke</creator><creator>Schultz, Peter G</creator><creator>Bollong, Michael J</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9287-6840</orcidid><orcidid>https://orcid.org/0000-0003-3188-1202</orcidid><orcidid>https://orcid.org/0000-0001-9439-1476</orcidid><orcidid>https://orcid.org/0000-0001-5171-7982</orcidid></search><sort><creationdate>20230516</creationdate><title>S-lactoyl modification of KEAP1 by a reactive glycolytic metabolite activates NRF2 signaling</title><author>Ko, Yeonjin ; 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Schultz; received January 13, 2023; accepted April 5, 2023; reviewed by Nathanael S. Gray and Kevan M. Shokat</notes><notes>1Y.K., M.H., and S.L. contributed equally to this work.</notes><abstract>KEAP1 (Kelch-like ECH-associated protein), a cytoplasmic repressor of the oxidative stress responsive transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2), senses the presence of electrophilic agents by modification of its sensor cysteine residues. In addition to xenobiotics, several reactive metabolites have been shown to covalently modify key cysteines on KEAP1, although the full repertoire of these molecules and their respective modifications remain undefined. Here, we report the discovery of sAKZ692, a small molecule identified by high-throughput screening that stimulates NRF2 transcriptional activity in cells by inhibiting the glycolytic enzyme pyruvate kinase. sAKZ692 treatment promotes the buildup of glyceraldehyde 3-phosphate, a metabolite which leads to S-lactate modification of cysteine sensor residues of KEAP1, resulting in NRF2-dependent transcription. 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| source | PubMed Central |
| subjects | Biological Sciences Cysteine Cysteine - metabolism Glyceraldehyde Glyceraldehyde 3-phosphate Glycolysis High-throughput screening Kelch-Like ECH-Associated Protein 1 - chemistry Metabolites NF-E2-Related Factor 2 - metabolism Oxidative metabolism Oxidative Stress Pyruvate kinase Pyruvic acid Reagents Residues Signal Transduction Xenobiotics |
| title | S-lactoyl modification of KEAP1 by a reactive glycolytic metabolite activates NRF2 signaling |
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