Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth
Summary: Lactate extensively associates with metabolic reprogramming, signal transduction, and immune modulation. Nevertheless, the regulatory role of lactate in immune sensing of cytosolic DNA remains uncertain. Here, we report that lactate serves as an initiator to facilitate proteasomal degradati...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-04-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725002128 |
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| author | Keqiang Rao Xinchao Zhang Yi Luo Qiang Xia Yuting Jin Jing He |
| author_facet | Keqiang Rao Xinchao Zhang Yi Luo Qiang Xia Yuting Jin Jing He |
| author_sort | Keqiang Rao |
| collection | DOAJ |
| description | Summary: Lactate extensively associates with metabolic reprogramming, signal transduction, and immune modulation. Nevertheless, the regulatory role of lactate in immune sensing of cytosolic DNA remains uncertain. Here, we report that lactate serves as an initiator to facilitate proteasomal degradation of cyclic GMP-AMP synthase (cGAS) independent of ubiquitin, thus repressing the production of interferon and contributing to tumor growth. Mechanistically, lactylation of K21 stimulates cGAS translocation from the nucleus to the proteasome for degradation, which is compromised by phosphorylation of PSMA4 S188 via disrupting its association with cGAS. Concurrently, lactylation of K415 rewires PIK3CB activity and impairs ULK1-driven phosphorylation of PSMA4 S188. Physiologically, lactylation of cGAS sustains tumor growth. Expression of cGAS correlates with the antitumor effect of the LDHA inhibitor FX11. Finally, the lactate-cGAS axis indicates a prognostic outcome of lung adenocarcinoma. Collectively, these findings not only put forth a mechanism of cGAS degradation but also unravel the clinical relevance of cGAS lactylation. |
| format | Article |
| id | doaj-art-8f8aa99843494201a8cdd81f3ef18ec2 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-8f8aa99843494201a8cdd81f3ef18ec22025-08-20T03:42:53ZengElsevierCell Reports2211-12472025-04-0144411544110.1016/j.celrep.2025.115441Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growthKeqiang Rao0Xinchao Zhang1Yi Luo2Qiang Xia3Yuting Jin4Jing He5Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China; Shanghai Institute of Transplantation, Shanghai 200120, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200120, ChinaDepartment of Pathology, College of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaDepartment of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China; Shanghai Institute of Transplantation, Shanghai 200120, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200120, ChinaDepartment of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China; Shanghai Institute of Transplantation, Shanghai 200120, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200120, China; Corresponding authorDepartment of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China; Shanghai Institute of Transplantation, Shanghai 200120, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai 200120, China; Corresponding authorDepartment of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China; Corresponding authorSummary: Lactate extensively associates with metabolic reprogramming, signal transduction, and immune modulation. Nevertheless, the regulatory role of lactate in immune sensing of cytosolic DNA remains uncertain. Here, we report that lactate serves as an initiator to facilitate proteasomal degradation of cyclic GMP-AMP synthase (cGAS) independent of ubiquitin, thus repressing the production of interferon and contributing to tumor growth. Mechanistically, lactylation of K21 stimulates cGAS translocation from the nucleus to the proteasome for degradation, which is compromised by phosphorylation of PSMA4 S188 via disrupting its association with cGAS. Concurrently, lactylation of K415 rewires PIK3CB activity and impairs ULK1-driven phosphorylation of PSMA4 S188. Physiologically, lactylation of cGAS sustains tumor growth. Expression of cGAS correlates with the antitumor effect of the LDHA inhibitor FX11. Finally, the lactate-cGAS axis indicates a prognostic outcome of lung adenocarcinoma. Collectively, these findings not only put forth a mechanism of cGAS degradation but also unravel the clinical relevance of cGAS lactylation.http://www.sciencedirect.com/science/article/pii/S2211124725002128CP: Cancer |
| spellingShingle | Keqiang Rao Xinchao Zhang Yi Luo Qiang Xia Yuting Jin Jing He Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth Cell Reports CP: Cancer |
| title | Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth |
| title_full | Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth |
| title_fullStr | Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth |
| title_full_unstemmed | Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth |
| title_short | Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth |
| title_sort | lactylation orchestrates ubiquitin independent degradation of cgas and promotes tumor growth |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725002128 |
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