Histidyl-tRNA synthetase (HARS)

Histidyl-tRNA synthetase (HARS) is a member of the class II aminoacyl-tRNA synthetase family, traditionally known for its cytoplasmic role in charging tRNA with histidine for protein synthesis (UniProt P12081). Beyond its canonical enzymatic activity, HARS is recognized for its significant extracellular roles and its involvement in autoimmune pathologies, notably serving as the Jo-1 autoantigen in inflammatory myopathies (PubMed: 25482370). Extracellular HARS and its truncated fragments, specifically those containing the 'iMod' domain, act as signaling molecules that modulate the immune system by interacting with receptors such as neuropilin-2 (NRP2) on myeloid cells (PubMed: 32544570). This interaction regulates the local inflammatory environment, particularly in lung tissues, making it a focus for treating interstitial lung diseases and sarcoidosis. In therapeutic development, HARS-derived biologics like efzofitimod utilize these non-canonical signaling pathways to suppress chronic inflammation without broad immunosuppression (PubMed: 35013038). Understanding the transition of HARS from an intracellular enzyme to an extracellular immunomodulator is critical for the development of targeted therapies in autoimmune and fibrotic conditions.

Other names

HARS1Histidine--tRNA ligaseJo-1 antigenHRSiMod domain (immunomodulatory domain)Cytoplasmic histidyl-tRNA synthetase

Efzofitimod is a selective neuropilin-2 (NRP2) agonist derived from a naturally occurring splice variant of HARS. It acts as an immunomodulator to downregulate inflammatory responses in the lung by binding to NRP2 on myeloid cells, effectively mimicking the natural extracellular signaling role of HARS fragments.