Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

Abstract

Despite remarkable advances in medical science, infection-associated diseases remain among the leading causes of death worldwide. There is a great deal of interest and concern at the rate at which new pathogens are emerging and causing significant human health problems. Expanding our understanding of how cells regulate signaling networks to defend against invaders and retain cell homeostasis will reveal promising strategies against infection. It has taken scientists decades to appreciate that eukaryotic aminoacyl-tRNA synthetases (ARSs) play a role as global cell signaling mediators to regulate cell homeostasis, beyond their intrinsic function as protein synthesis enzymes. Recent discoveries revealed that ubiquitously expressed standby cytoplasmic ARSs sense and respond to danger signals and regulate immunity against infections, indicating their potential as therapeutic targets for infectious diseases. In this review, we discuss ARS-mediated anti-infectious signaling and the emerging role of ARSs in antimicrobial immunity. In contrast to their ability to defend against infection, host ARSs are inevitably co-opted by viruses for survival and propagation. We therefore provide a brief overview of the communication between viruses and the ARS system. Finally, we discuss encouraging new approaches to develop ARSs as therapeutics for infectious diseases.

Roles of aminoacyl-tRNA synthetases in immune regulation and immune diseases

“…Of note, murine Jo-1 induced autoreactive B and T cells targeting its own epitopes, and the epitope spreading occurred uniformly 8 weeks after the single immunization, suggesting that autoantibody Jo-1 was able to drive a sustained immune response. When PBMCs and bronchoalveolar lavage fluid (BALF) cells from ASSD patients were stimulated with HisRS or a HisRS-derived peptide (HisRS [11][12][13][14][15][16][17][18][19][20][21][22][23] ), the expression of CD40L in CD4 + T cells from the corresponding compartments was upregulated 78 . Compared with PBMCs, BALF CD4 + T cells showed a remarkable Th1 phenotype after stimulation, such as the production of more IFN-γ and IL-2, indicating the presence of HisRS-specific CD4 + T cells in the blood and lung of patients with ASSD.…”

“…For example, seryl-tRNA synthetase (SerRS) could bind to transcription factor Yin Yang 1 (YY1) to form a SerRS/YY1 complex, which interacted with distal cis-regulatory elements and then negatively regulated vascular endothelial cell growth factor A transcription during angiogenesis 10 . Furthermore, ARSs are emerging as multifaceted molecules participating in immune regulation and immune diseases [11][12][13] . It has been found that the pathogenic variants in lysyl-tRNA synthetase (KARS) cause a progressive leukodystrophy, and the patients exhibit severe phenotypes including developmental delay or arrest, deafness, and immunological abnormalities 14 .…”

When a common biological role does not imply common disease outcomes: Disparate pathology linked to human mitochondrial aminoacyl-tRNA synthetases

“…Recent discoveries that human cytosolic aaRSs and fragments thereof are involved in multiple signaling pathways and linked to numerous diseases (79 -83), ranging from cancer to Charcot-Marie-Tooth disease, strengthen this view. These enzymes have been found to act as procytokines (84,85) and partners in pathways, including tumorigenesis, immune response, and inflammation (81,82,86). Given this functional expansion among their cytosolic homologs, it is likely that similar noncanonical functions have also evolved in the mt-aaRSs.…”

Role of host tRNAs and aminoacyl-tRNA synthetases in retroviral replication

“…They play unique regulatory roles in cellular signaling pathways (22,130), and some ARSs are even secreted and act as cytokines and chemokines (131,132). The roles that ARSs play in response to viral infection and the immune response make them potential therapeutic targets and diagnostic biomarkers (133). Interestingly, many ARSs have been identified in multi-omic studies focusing on retroviral replication.…”