For decades, lactate has been considered a byproduct of glycolysis. The lactate shuttle hypothesis shifted the lactate paradigm, demonstrating that lactate not only plays important roles in cellular metabolism but also cellular communications, which can transcend compartment barriers and can occur within and among different cells, tissues and organs. Recently, the discovery that lactate can induce a novel post-translational modification, named lysine lactylation (Kla), brings forth a new avenue to study nonmetabolic functions for lactate, which has inspired a ‘gold rush’ of academic and commercial interest. Zhang et al. first showed that Kla is manifested in histones as epigenetic marks, and then mounting evidences demonstrated that Kla also occurs in diverse non-histone proteins. The widespread Kla faithfully orchestrates numerous biological processes, such as transcription, metabolism and inflammatory responses. Notably, dysregulation of Kla touches a myriad of pathological processes. In this review, we comprehensively reviewed and curated the existing literature to retrieve the new identified Kla sites on both histones and non-histone proteins and summarized recent major advances toward its regulatory mechanism. We also thoroughly investigated the function and underlying signaling pathway of Kla and comprehensively summarize how Kla regulates various biological processes in normal physiological states. In addition, we also further highlight the effects of Kla in the development of human diseases including inflammation response, tumorigenesis, cardiovascular and nervous system diseases and other complex diseases, which might potentially contribute to deeply understanding and interpreting the mechanism of its pathogenicity.

中文翻译：

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健康和疾病中普遍存在的蛋白质乳酰化

几十年来，乳酸一直被认为是糖酵解的副产品。乳酸穿梭假说改变了乳酸范式，证明乳酸不仅在细胞代谢中发挥重要作用，而且在细胞通讯中发挥重要作用，细胞通讯可以超越隔室屏障，可以发生在不同细胞、组织和器官内部和之间。最近，乳酸可以诱导一种新的翻译后修饰，即赖氨酸乳酰化（Kla）的发现，为研究乳酸的非代谢功能开辟了一条新途径，激发了学术和商业兴趣的“淘金热”。张等人。首先表明 Kla 在组蛋白中表现为表观遗传标记，然后越来越多的证据表明 Kla 也出现在多种非组蛋白中。广泛分布的 Kla 忠实地协调了许多生物过程，例如转录、新陈代谢和炎症反应。值得注意的是，Kla 的失调涉及多种病理过程。在这篇综述中，我们全面回顾和整理了现有文献，以检索组蛋白和非组蛋白上新鉴定的 Kla 位点，并总结了其调控机制的最新主要进展。我们还深入研究了Kla的功能和潜在信号通路，全面总结了Kla在正常生理状态下如何调节各种生物过程。此外，我们还进一步强调了Kla在人类疾病发展中的作用，包括炎症反应、肿瘤发生、心血管和神经系统疾病以及其他复杂疾病，这可能有助于深入理解和解释其致病机制。