Histidyl-tRNA synthetase 1 (HARS1) (HARS1)

Histidyl-tRNA synthetase 1 (HARS1) is a dual-function protein belonging to the aminoacyl-tRNA synthetase family, primarily known for its canonical role in cytoplasmic protein synthesis by catalyzing the attachment of histidine to its cognate tRNA (UniProt P12081) [1]. Beyond this intracellular role, HARS1 is secreted into the extracellular environment where it functions as an immunomodulatory signaling molecule, a mechanism referred to as the Resokine pathway (aTyr Pharma) [2]. In the extracellular space, HARS1 or its specific fragments (such as iHARS) interact with the Neuropilin-2 (NRP2) receptor on myeloid cells, including macrophages and dendritic cells, to downregulate inflammatory signaling and promote tissue homeostasis (Frontiers in Immunology, 2022) [3]. This pathway is critically involved in the pathogenesis of interstitial lung diseases (ILD) and autoimmune conditions like sarcoidosis and antisynthetase syndrome, where HARS1 also serves as a major autoantigen known as the Jo-1 antigen (StatPearls) [4]. Therapeutic development focuses on modulating this pathway; for instance, efzofitimod is a clinical-stage HARS1-derived fusion protein designed to act as a selective NRP2 agonist to treat chronic inflammatory lung diseases (ClinicalTrials.gov) [5].

Other names

HARSHistidine--tRNA ligaseHRSJo-1 antigenResokineCytoplasmic histidyl-tRNA synthetase

Selective Neuropilin-2 (NRP2) agonist/modulator that downregulates activated myeloid cells to reduce inflammatory cytokine release and promote tissue repair (aTyr Pharma; Frontiers in Immunology) [2, 3].