Jumonji domain-containing protein 6 (JMJD6) (JMJD6)

Jumonji domain-containing protein 6 (JMJD6), historically known as the Phosphatidylserine receptor (PSR), is a nuclear enzyme that functions as a histone arginine demethylase and a lysyl hydroxylase. Although it was initially identified as a cell surface receptor responsible for the recognition and engulfment of phosphatidylserine (PS) on apoptotic cells, subsequent research demonstrated that JMJD6 is primarily localized to the nucleus and does not directly bind PS on the cell surface. Instead, the recognition of PS during efferocytosis is mediated by a diverse group of receptors, including the TAM (Tyro3, Axl, MerTK) and TIM (TIM-1, TIM-3, TIM-4) families. Despite this misidentification, JMJD6 has emerged as a significant therapeutic target in oncology, as its overexpression in various cancers promotes tumor progression, metastasis, and chemoresistance through the regulation of RNA splicing and epigenetic modifications. Current therapeutic strategies targeting the PS-receptor axis include monoclonal antibodies against PS itself, such as bavituximab, and inhibitors of the functional PS receptors like Axl and TIM-3. Research into specific small molecule inhibitors of JMJD6's enzymatic activity is also ongoing to address its role in cancer and viral infections. The target's involvement in developmental processes is highlighted by the fact that JMJD6 deficiency leads to neonatal lethality in animal models. Overall, while the "Phosphatidylserine receptor" name persists, the target's clinical relevance has shifted from cell surface engulfment to nuclear gene regulation.

Other names

Phosphatidylserine receptorPSRPTDSRPtdSerRHistone arginine demethylase JMJD6Lysyl-hydroxylase JMJD6

Inhibition of histone demethylase and lysyl hydroxylase activity; blockade of phosphatidylserine-mediated immunosuppressive signaling; modulation of efferocytosis.