JMJD5 regulates metabolism by inhibiting the Arginine Methyltransferase PRMT6

2-Oxoglutarate-dependent Dioxygenases (2OGDDs) are a family of enzymes requiring molecular oxygen, 2-oxoglutarate, reduced iron, and ascorbic acid to function. This dependency renders them key sensors of the cell's metabolic state, driving crucial functions when oxygen or metabolic homeostasis is perturbed, including adaptation to low oxygen, epigenetic control of gene transcription, and the reshaping of metabolic pathways. Jumonji-C (JmjC) domain-containing protein 5 (JMJD5), a 2OGDD that alters epigenetic marks, is essential for DNA damage repair and is a key regulator of cell metabolism. Notably, JMJD5 is often lost in hepatocellular carcinoma, which correlates with poor overall survival. Despite its biological significance, the molecular functions of JMJD5 remain unresolved, and its physiological targets are elusive. Here, we identify and characterise a novel signalling pathway where JMJD5 hydroxylates an arginine residue on the protein ISY1. This modification enables ISY1 to bind to and reduce the activity of Protein Arginine N-methyltransferase 6 (PRMT6). Significantly, the inactivation of PRMT6 rescues the majority of the molecular phenotype driven by JMJD5 loss, establishing the JMJD5-ISY1-PRMT6 pathway as the principal executor of JMJD5's enzymatic function. This signalling pathway clarifies existing controversies regarding JMJD5's function and identifies PRMT6 as a potential therapeutic target for treating cancers that lack JMJD5.