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Elongator is required for pattern recognition receptor and type I interferon signaling in macrophages.
J. Biol. Chem. 301:110916 (2025)
Innate immune detection of pathogens by macrophages requires a rapid and large scale mobilisation of cellular resources towards an appropriate immune response, mainly involving altered protein expression. Pathogen recognition is mediated by pattern recognition receptor (PRR) sensing of conserved microbial patterns, a prototypical example being recognition of lipopolysaccharide (LPS) by TLR4. This leads to induction of pro-inflammatory cytokines, chemokines and type I interferons (IFN Is) which together mobilise appropriate anti-pathogen responses. IFN Is signal to transcription of IFN-stimulated genes (ISG) which encode numerous anti-viral proteins. Many studies have contributed to a detailed understanding of transcriptional regulation of mRNA during such responses, however much less is known about the contribution of protein complexes required for mRNA translation. Here we examine the role of the evolutionarily conserved elongator complex in PRR signaling in macrophages. Elongator modifies tRNAs at U34 to facilitate more efficient wobble interactions between tRNAs and mRNA codons. In macrophages, deletion of Elp3, the catalytic subunit of elongator, led to an impaired PRR-IFN I-ISG signaling axis. The ELP3-dependent LPS-stimulated proteome was enriched with proteins involved in PRR activation of IRFs and in IFN signalling. Specifically, ELP3 was required for expression of key transcription factors regulating this axis, for TYK2-dependent IFN-I signaling and for IRF3 activation for some, but not all, PRRs. Importantly, ELP3 was also necessary for innate immune gene induction following virus infection. These data reveal specific roles for elongator in PRR signaling and illustrate the underappreciated importance of translational regulation in optimal anti-pathogen innate immune responses.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Innate Immunity ; Stat Transcription Factor ; Toll-like Receptor 4 (tlr4) ; Elongator ; Interferon ; Interferon Regulatory Factor (irf) ; Lipopolysaccharide (lps) ; Macrophage ; Pattern Recognition Receptor (prr) ; Virus; Transfer-rna Modification; Wobble; Ikbkap
ISSN (print) / ISBN
0021-9258
e-ISSN
1083-351X
Quellenangaben
Volume: 301,
Issue: 12,
Article Number: 110916
Publisher
American Society for Biochemistry and Molecular Biology
Publishing Place
Radarweg 29, 1043 Nx Amsterdam, Netherlands
Reviewing status
Peer reviewed
Institute(s)
Institute of Virology (VIRO)
Grants
Center for Immunology of Viral Infections (CiViA)
Prevention of Pandemic-infection-associated Pathology Munich-P3M"
German Research Foundation (DFG)
Research Ireland
Prevention of Pandemic-infection-associated Pathology Munich-P3M"
German Research Foundation (DFG)
Research Ireland