Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition
Abstract Hypoxia-inducible factor 1α (HIF-1α) is a master regulator of cellular adaptation to hypoxia. Although prolyl hydroxylation-mediated degradation via the von Hippel–Lindau (VHL) ubiquitination complex is a well-established regulatory mechanism, the role of lactate-induced posttranslational m...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-08-01
|
| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-025-02366-x |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849234452494942208 |
|---|---|
| author | Chengyu Li Chen Fu Wenhan Zhou Hongmin Li Zhaojun Liu Gang Wu Tong He Ming Shen Honglin Liu |
| author_facet | Chengyu Li Chen Fu Wenhan Zhou Hongmin Li Zhaojun Liu Gang Wu Tong He Ming Shen Honglin Liu |
| author_sort | Chengyu Li |
| collection | DOAJ |
| description | Abstract Hypoxia-inducible factor 1α (HIF-1α) is a master regulator of cellular adaptation to hypoxia. Although prolyl hydroxylation-mediated degradation via the von Hippel–Lindau (VHL) ubiquitination complex is a well-established regulatory mechanism, the role of lactate-induced posttranslational modifications in HIF-1α stabilization remains incompletely understood. Here, we demonstrate that lactate induces lysine lactylation of HIF-1α at distinct residues across species—specifically, K644 in mice and K12 in humans and pigs—to increase protein stability by impairing VHL recognition. Mass spectrometry and mutagenesis analyses revealed that lactylation at these sites reduces K48-linked ubiquitination and proteasomal degradation, even when HIF-1α is hydroxylated. Structural modeling and functional assays revealed that lactylation sterically hinders VHL binding without affecting hydroxylation. Notably, lactylated HIF-1α exhibited increased transcriptional activity, as evidenced by increased promoter occupancy and upregulation of hypoxia-responsive genes (Vegfa, Glut1). Cross-species comparisons highlighted evolutionary divergence in lactylation sites while preserving the functional conservation of this modification. Our findings reveal that lactylation is a universal regulatory mechanism that overrides classical hydroxylation-dependent degradation, expanding our understanding of metabolic control over hypoxic signaling. |
| format | Article |
| id | doaj-art-7d26f55ab9e44af4950a957d7d95d7f0 |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-7d26f55ab9e44af4950a957d7d95d7f02025-08-20T04:03:07ZengBMCCell Communication and Signaling1478-811X2025-08-0123112010.1186/s12964-025-02366-xLactylation modification of HIF-1α enhances its stability by blocking VHL recognitionChengyu Li0Chen Fu1Wenhan Zhou2Hongmin Li3Zhaojun Liu4Gang Wu5Tong He6Ming Shen7Honglin Liu8College of Animal Science and Technology, Nanjing Agricultural UniversityCollege of Animal Science and Technology, Nanjing Agricultural UniversityCollege of Animal Science and Technology, Nanjing Agricultural UniversityCollege of Animal Science and Technology, Nanjing Agricultural UniversityCollege of Animal Science and Technology, Nanjing Agricultural UniversityCollege of Animal Science and Technology, Nanjing Agricultural UniversityCollege of Animal Science and Technology, Nanjing Agricultural UniversityCollege of Animal Science and Technology, Nanjing Agricultural UniversityCollege of Animal Science and Technology, Nanjing Agricultural UniversityAbstract Hypoxia-inducible factor 1α (HIF-1α) is a master regulator of cellular adaptation to hypoxia. Although prolyl hydroxylation-mediated degradation via the von Hippel–Lindau (VHL) ubiquitination complex is a well-established regulatory mechanism, the role of lactate-induced posttranslational modifications in HIF-1α stabilization remains incompletely understood. Here, we demonstrate that lactate induces lysine lactylation of HIF-1α at distinct residues across species—specifically, K644 in mice and K12 in humans and pigs—to increase protein stability by impairing VHL recognition. Mass spectrometry and mutagenesis analyses revealed that lactylation at these sites reduces K48-linked ubiquitination and proteasomal degradation, even when HIF-1α is hydroxylated. Structural modeling and functional assays revealed that lactylation sterically hinders VHL binding without affecting hydroxylation. Notably, lactylated HIF-1α exhibited increased transcriptional activity, as evidenced by increased promoter occupancy and upregulation of hypoxia-responsive genes (Vegfa, Glut1). Cross-species comparisons highlighted evolutionary divergence in lactylation sites while preserving the functional conservation of this modification. Our findings reveal that lactylation is a universal regulatory mechanism that overrides classical hydroxylation-dependent degradation, expanding our understanding of metabolic control over hypoxic signaling.https://doi.org/10.1186/s12964-025-02366-xHIF-1αLactateLactylationUbiquitinationHydroxylationVHL |
| spellingShingle | Chengyu Li Chen Fu Wenhan Zhou Hongmin Li Zhaojun Liu Gang Wu Tong He Ming Shen Honglin Liu Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition Cell Communication and Signaling HIF-1α Lactate Lactylation Ubiquitination Hydroxylation VHL |
| title | Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition |
| title_full | Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition |
| title_fullStr | Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition |
| title_full_unstemmed | Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition |
| title_short | Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition |
| title_sort | lactylation modification of hif 1α enhances its stability by blocking vhl recognition |
| topic | HIF-1α Lactate Lactylation Ubiquitination Hydroxylation VHL |
| url | https://doi.org/10.1186/s12964-025-02366-x |
| work_keys_str_mv | AT chengyuli lactylationmodificationofhif1aenhancesitsstabilitybyblockingvhlrecognition AT chenfu lactylationmodificationofhif1aenhancesitsstabilitybyblockingvhlrecognition AT wenhanzhou lactylationmodificationofhif1aenhancesitsstabilitybyblockingvhlrecognition AT hongminli lactylationmodificationofhif1aenhancesitsstabilitybyblockingvhlrecognition AT zhaojunliu lactylationmodificationofhif1aenhancesitsstabilitybyblockingvhlrecognition AT gangwu lactylationmodificationofhif1aenhancesitsstabilitybyblockingvhlrecognition AT tonghe lactylationmodificationofhif1aenhancesitsstabilitybyblockingvhlrecognition AT mingshen lactylationmodificationofhif1aenhancesitsstabilitybyblockingvhlrecognition AT honglinliu lactylationmodificationofhif1aenhancesitsstabilitybyblockingvhlrecognition |