Hepatitis E virus (HEV)
infection has been shown to activate
NOD-like receptor family pyrin domain-containing 3 (NLRP3)
inflammasome in macrophages, a key mechanism of causing pathological
inflammation, but the mechanisms regulating this response remain poorly understood. Here, we report that the mature tRNAome dynamically responds to HEV
infection in macrophages. This directs IL-1β expression, the hallmark of NLRP3
inflammasome activation, at
mRNA and
protein levels. Conversely, pharmacological inhibition of
inflammasome activation abrogates HEV-provoked tRNAome remodeling, revealing a reciprocal interaction between the mature tRNAome and the NLRP3
inflammasome response. Remodeling the tRNAome results in improved decoding of
codons directing
leucine- and
proline synthesis, which are the major
amino acid constituents of IL-1β
protein, whereas genetic or functional interference with tRNAome-mediated
leucine decoding impairs
inflammasome activation. Finally, we demonstrated that the mature tRNAome also actively responds to
lipopolysaccharide (a key component of gram-negative bacteria)-triggered
inflammasome activation, but the response dynamics and mode of actions are distinct from that induced by HEV
infection. Our findings thus reveal the mature tRNAome as a previously unrecognized but essential mediator of host response to pathogens and represent a unique target for developing anti-inflammatory
therapeutics.