Protein Lactylation Critically Regulates Energy Metabolism in the Protozoan Parasite Trypanosoma brucei

Abstract

Lysine lactylation has been recognized as a novel post-translational modification occurring on histones. However, lactylation in non-histone proteins, especially in proteins of early branching organisms, is not well understood. Energy metabolism and the histone repertoire in the early diverging protozoan parasite <i>Trypanosoma brucei</i>, the causative agent of African trypanosomiasis, markedly diverge from those of conventional eukaryotes. Here, we present the first exhaustive proteome-wide investigation of lactylated sites in <i>T. brucei</i>. We identified 387 lysine-lactylated sites in 257 proteins of various cellular localizations and biological functions. Further, we revealed that glucose metabolism critically regulates protein lactylation in <i>T. brucei</i> although the parasite lacks lactate dehydrogenase. However, unlike mammals, increasing the glucose concentration reduced the level of lactate, and protein lactylation decreased in <i>T. brucei via</i> a unique lactate production pathway. In addition to providing a valuable resource, these foregoing data reveal the regulatory roles of protein lactylation of trypanosomes in energy metabolism and gene expression.