LHPP Attenuates Lipid Dysfunction of Uveal Melanoma by Relieving the Histidine Phosphorylation of ACO2

Histidine phosphorylation, the neglected but vital phosphoproteome, is a reversible posttranslational modification catalyzed by histidine kinases and erased by phosphohistidine (pHis) phosphatases (e.g., LHPP). Traditional types of phosphorylation have been implicated with the deadliest adult ocular tumor uveal melanoma (UM), which is lipid metabolism dysfunction related. However, the role of histidine phosphorylation in UM remains unknown. Here, up-regulated histidine phosphorylation is associated with poor UM prognosis. Reversal of histidine phosphorylation by LHPP exerts therapeutic effects. Mechanistically, we identified LHPP as metabolically related protein with mitochondrial targeting sequence. LHPP interacts and reduces excessive histidine phosphorylation of mitochondrial aconitase ACO2 at H73 site, thus restoring ACO2 enzymatic activity and mitochondrial citrate transit in TCA cycle. Reduction of citrate accumulation attenuates overloaded lipid synthesis. Besides, genetic ablation of LHPP in mouse eye exhibits abnormal lipid metabolism. These findings illustrate the antagonistic roles of oncogenic histidine phosphorylation and therapeutic mitochondrial LHPP and provide metabolic insight of pHis modification in ocular diseases.