Cyclic immonium ion of lactyllysine reveals widespread lactylation in the human proteome

Wan, Ning; Wang, Nian; Yu, Shi; Zhang, Hanqing; Tang, Shuo; Wang, Dexiang; Lu, Wenjie; Li, Huanhuan; Delafield, Daniel G.; Kong, Ying; Wang, Xinmiao; Shao, Chen; Lv, Langlang; Wang, Guangji; Tan, Renxiang; Wang, Nanxi; Hao, Haiping; Ye, Hui

doi:10.1038/s41592-022-01523-1

Cited by 111 publications

(76 citation statements)

References 40 publications

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“…They unveiled a widespread lactylation proteome beyond histones in both cytoplasm and nucleus from not only the enriched lactylproteome but also the existing unenriched human proteome resources. 232 With the help of other chemical tools such as alkynyl-functionalized bioorthogonal chemical reporter (YnLac), nonhistone Klac has also been reported by other studies in recent years. 233 , 234 The limited studies on nonhistone Klac have indicated its critical role in tumor, polymicrobial sepsis and retinopathy.…”

Section: Protein Acylation In Human Diseasesmentioning

confidence: 95%

Protein acylation: mechanisms, biological functions and therapeutic targets

Shang

Liu

Hua

2022

Sig Transduct Target Ther

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Metabolic reprogramming is involved in the pathogenesis of not only cancers but also neurodegenerative diseases, cardiovascular diseases, and infectious diseases. With the progress of metabonomics and proteomics, metabolites have been found to affect protein acylations through providing acyl groups or changing the activities of acyltransferases or deacylases. Reciprocally, protein acylation is involved in key cellular processes relevant to physiology and diseases, such as protein stability, protein subcellular localization, enzyme activity, transcriptional activity, protein–protein interactions and protein–DNA interactions. Herein, we summarize the functional diversity and mechanisms of eight kinds of nonhistone protein acylations in the physiological processes and progression of several diseases. We also highlight the recent progress in the development of inhibitors for acyltransferase, deacylase, and acylation reader proteins for their potential applications in drug discovery.

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Section: Protein Acylation In Human Diseasesmentioning

confidence: 95%

Protein acylation: mechanisms, biological functions and therapeutic targets

Shang

Liu

Hua

2022

Sig Transduct Target Ther

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“…Besides histone lactylation, a sepsis study reported that HMGB1 lactylation increasing its exocytosis from macrophage, which provided a new way to combat sepsis in lactate-related pathway (Yang et al, 2022). The latest report further confirmed that lactylation was widespread in the human proteome and probably played an important regulatory role (Wan et al, 2022). These findings provoke us to revisit the role of lactate and anticipate the effect of lactylation in cerebral ischemia.…”

Section: Introductionmentioning

confidence: 91%

Lactate-derived HDAC6 Lactylation as a new target for neuronal protection in cerebral ischemic reperfusion injury

Cao

Hong

Zeng

et al. 2022

Preprint

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Lactylation is a newly found lactate-derived post-translational modification, which is firstly reported on histone protein lysine residues to regulate gene expression. Here, we provided evidence that higher serum lactate level was possibly associated with better prognosis in ischemic stroke patients. Meanwhile, inhibition of endogenous lactate increased the infarct volume and decreased protein pan-lactylation in the affected brain tissue in cerebral ischemia mice. We further demonstrated that downregulating lactylation level of Hdac6 (Histone Deacetylase 6) in neurons exacerbated ischemic neuronal injury. The underlying mechanisms involved Hdac6 lactylation disturbing calcium homeostasis through binding BiP (Binding immunoglobulin protein), an endoplasmic reticulum-related protein. Collectively, our findings identified a new effect of lactate for neuroprotection through Hdac6 lactylation during cerebral ischemic reperfusion injury which introduced a potential therapeutic approach against ischemic stroke.

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“…Beyond mediating immunosuppression, the mechanisms and functional effects of histone/protein lactylation are becoming progressively unveiled [ 283 ]. For example, it is now known that the acetyltransferase p300 mediates histone lactylation, while HDAC1-3 serves as delactylases [ 284 ].…”

Section: Metabolites and Gene Regulationmentioning

confidence: 99%

“…For example, it is now known that the acetyltransferase p300 mediates histone lactylation, while HDAC1-3 serves as delactylases [ 284 ]. Furthermore, it has been shown that lactylation on the glycolytic enzyme ALDOA serves to allosterically inhibit its enzymatic activity, potentially mediating a negative feedback loop for the glycolysis pathway in the presence of excess lactic acid [ 283 ]. Finally, the functional relevance of lactylation has also been reported in RNA splicing, neurodevelopment, osteoblast differentiation, and cancer progression [ 285 , 286 , 287 , 288 ].…”

Section: Metabolites and Gene Regulationmentioning

confidence: 99%

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

et al. 2022

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There is an urgent need for exploring new actionable targets other than androgen receptor to improve outcome from lethal castration-resistant prostate cancer. Tumor metabolism has reemerged as a hallmark of cancer that drives and supports oncogenesis. In this regard, it is important to understand the relationship between distinctive metabolic features, androgen receptor signaling, genetic drivers in prostate cancer, and the tumor microenvironment (symbiotic and competitive metabolic interactions) to identify metabolic vulnerabilities. We explore the links between metabolism and gene regulation, and thus the unique metabolic signatures that define the malignant phenotypes at given stages of prostate tumor progression. We also provide an overview of current metabolism-based pharmacological strategies to be developed or repurposed for metabolism-based therapeutics for castration-resistant prostate cancer.

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Cyclic immonium ion of lactyllysine reveals widespread lactylation in the human proteome

Cited by 111 publications

References 40 publications

Protein acylation: mechanisms, biological functions and therapeutic targets

Protein acylation: mechanisms, biological functions and therapeutic targets

Lactate-derived HDAC6 Lactylation as a new target for neuronal protection in cerebral ischemic reperfusion injury

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

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