Histidyl-tRNA synthetase (HARS) (HARS)

Histidyl-tRNA synthetase (HARS) is a cytoplasmic enzyme that plays a fundamental role in protein synthesis by catalyzing the attachment of histidine to its corresponding tRNA molecule [1]. In addition to its canonical enzymatic function, HARS is recognized as a potent autoantigen, specifically the Jo-1 antigen, which is the most common target of autoantibodies in patients with antisynthetase syndrome (ASS) [2, 4]. The binding of anti-Jo-1 autoantibodies to full-length HARS is a defining feature of this systemic autoimmune disease, which manifests as inflammatory myopathy, interstitial lung disease, and polyarthritis [4]. Beyond its role as an antigen, HARS possesses non-canonical signaling properties; for instance, its WHEP domain can act as a cytokine-like fragment that recruits immune cells via interactions with receptors like neuropilin-2, potentially driving chronic inflammation [3, 5]. Therapeutic strategies for Jo-1-associated diseases primarily involve broad immunosuppression using agents like rituximab to deplete B-cells or JAK inhibitors to block downstream inflammatory signaling [2]. Experimental therapies such as efzofitimod, a HARS-derived immunomodulator, are currently being investigated to target the HARS-neuropilin-2 axis to treat associated interstitial lung disease [5].

Other names

Jo-1 antigenHistidine--tRNA ligaseHARS1HRSAnti-Jo-1 autoantigen

B-cell depletion, T-cell costimulation blockade, JAK/STAT inhibition, DNA alkylation, Inosine monophosphate dehydrogenase inhibition, Neuropilin-2 agonism