Mechanistic perspectives on anti-aminoacyl-tRNA synthetase syndrome. Issue 3 (March 2023)

• Record Type: Journal Article
• Authors: Kanaji, Sachiko; Chen, Wenqian; Morodomi, Yosuke; Shapiro, Ryan; Kanaji, Taisuke; Yang, Xiang-Lei
• Is Part Of: Trends in biochemical sciences. Volume 48:Issue 3(2023)
• Page Start: 288
• Page End: 302
• Publication Date: 2023-03
• Subjects: autoantigen -- HisRS -- WHEP domain -- tRNA -- extracellular vesicle -- immune complex; Biochemistry -- Periodicals; 572
• DOI: 10.1016/j.tibs.2022.09.011
• Languages: English
• ISSNs: 0968-0004

Abstract

Abstract : Antisynthetase syndrome (ASSD) is an autoimmune disease characterized by circulating autoantibodies against one of eight aminoacyl-tRNA synthetases (aaRSs). Although these autoantibodies are believed to play critical roles in ASSD pathogenesis, the nature of their roles remains unclear. Here we describe ASSD pathogenesis and discuss ASSD-linked aaRSs – from the WHEP domain that may impart immunogenicity to the role of tRNA in eliciting the innate immune response and the secretion of aaRSs from cells. Through these explorations, we propose that ASSD pathogenesis involves the tissue-specific secretion of aaRSs and that extracellular tRNAs or tRNA fragments and their ability to engage Toll-like receptor signaling may be important disease factors. Highlights: Antisynthetase syndrome (ASSD) autoantibodies target one of eight cytoplasmic tRNA synthetases, which is usually not associated with the multisynthetase complex and most likely to be a class IIa tRNA synthetase. Tissue-specific secretion of tRNA synthetases and their cognate tRNA may contribute to their selective involvement in ASSD. Histidyl-tRNA synthetase (HisRS) is the predominant autoantigen in ASSD, and the major epitope resides in the evolutionarily new WHEP domain, which is not found in most other ASSD-linked aminoacyl-tRNA synthetases. The HisRS WHEP domain (with different C-terminus) reportedly can elicit either immune activation or immune-suppressive activities. The immune-suppressive activity of an HisRS WHEP-containing splice variant is being developed at clinical phases for treating lung inflammation.