Tryptophanyl-tRNA synthetase (WRS) is one of the aminoacyl-
tRNA synthetases (ARSs) that possesses noncanonical functions. Full-length WRS is released during
bacterial infection and primes the
Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex to elicit innate immune responses. However, the role of WRS in
viral infection remains unknown. Here, we show that full-length WRS is secreted by immune cells in the early phase of
viral infection and functions as an
antiviral cytokine. Treatment of cells with recombinant WRS
protein promotes the production of inflammatory
cytokines and
type I interferons (IFNs) and curtails virus replication in THP-1 and Raw264.7 cells but not in TLR4-/- or MD2-/- bone marrow-derived macrophages (BMDMs). Intravenous and
intranasal administration of recombinant WRS
protein induces an innate immune response and blocks viral replication in vivo These findings suggest that secreted full-length WRS has a noncanonical role in inducing innate immune responses to
viral infection as well as to
bacterial infection.IMPORTANCE ARSs are essential
enzymes in translation that link specific
amino acids to their cognate tRNAs. In higher eukaryotes, some ARSs possess additional, noncanonical functions in the regulation of cell metabolism. Here, we report a novel noncanonical function of WRS in
antiviral defense. WRS is rapidly secreted in response to
viral infection and primes the innate immune response by inducing the secretion of proinflammatory
cytokines and type I IFNs, resulting in the inhibition of virus replication both in vitro and in vivo Thus, we consider WRS to be a member of the
antiviral innate immune response. The results of this study enhance our understanding of host defense systems and provide additional information on the noncanonical functions of ARSs.