Comprehensive analysis of lysine lactylation in Frankliniella occidentalis

The Warburg effect, originally describing augmented lactogenesis in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, macrophage polarization, and T-cell activation. This phenomenon is intimately linked with multiple diseases including neoplasia, sepsis, and autoimmune diseases 1,2 . Lactate, a compound generated during Warburg effect, is widely known as an energy source and metabolic byproduct. However, its non-metabolic functions in physiology and disease remain unknown. Here we report lactate-derived histone lysine lactylation as a new epigenetic modification and demonstrate that histone lactylation directly stimulates gene transcription from chromatin. In total, we identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce production of lactate through glycolysis that in turn serves as precursor for stimulating histone lactylation. Using bacterially exposed M1 macrophages as a model system, we demonstrate that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, elevated histone lactylation induces homeostatic genes involved in wound healing including arginase 1. Collectively, our results suggest the presence of an endogenous “lactate clock” in bacterially challenged M1 macrophages that turns on gene expression to promote homeostasis. Histone lactylation thus represents a new avenue for understanding the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer.

During the past 20 years there has been a dramatic resurgence or emergence of epidemic arboviral diseases affecting both humans and domestic animals. These epidemics have been caused primarily by viruses thought to be under control such as dengue, Japanese encephalitis, yellow fever, and Venezuelan equine encephalitis, or viruses that have expanded their geographic distribution such as West Nile and Rift Valley fever. Several of these viruses are presented as case studies to illustrate the changing epidemiology. The factors responsible for the dramatic resurgence of arboviral diseases in the waning years of the 20th century are discussed, as is the need for rebuilding the public health infrastructure to deal with epidemic vector-borne diseases in the 21st century.

We hypothesized that in addition to serving as a fuel source and gluconeogenic precursor, lactate anion (La-) is a signaling molecule. Therefore, we screened genome-wide responses of L6 cells to elevated (10 and 20 mM) sodium-La- added to buffered, high-glucose media. Lactate increased reactive oxygen species (ROS) production and up-regulated 673 genes, many known to be responsive to ROS and Ca2+. The induction of genes encoding for components of the mitochondrial lactate oxidation complex was confirmed by independent methods (PCR and EMSA). Specifically, lactate increased monocarboxylate transporter-1 (MCT1) mRNA and protein expression within 1 h and cytochrome c oxidase (COX) mRNA and protein expression in 6 h. Increases in COX coincided with increases in peroxisome proliferator activated-receptor gamma coactivator-1alpha (PGC1alpha) expression and the DNA binding activity of nuclear respiratory factor (NRF)-2. We conclude that the lactate signaling cascade involves ROS production and converges on transcription factors affecting mitochondrial biogenesis.