Lysyl-tRNA synthetase produces diadenosine tetraphosphate to curb STING-dependent inflammation

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DOI

  • J. Guerra, Universite de Montpellier
  • ,
  • A. L. Valadao, Universite de Montpellier
  • ,
  • D. Vlachakis, Agricultural University of Athens
  • ,
  • K. Polak, Institut de Génétique Humaine, Universite de Montpellier
  • ,
  • I. K. Vila, Universite de Montpellier
  • ,
  • C. Taffoni, Universite de Montpellier
  • ,
  • T. Prabakaran
  • A. S. Marriott, Edge Hill University
  • ,
  • R. Kaczmarek, Center for Molecular and Macromolecular Studies of the Polish Academy of Sciences
  • ,
  • A. Houel, Universite Paris-Saclay
  • ,
  • B. Auzemery, Universite de Montpellier
  • ,
  • S. Déjardin, Universite de Montpellier
  • ,
  • P. Boudinot, Universite Paris-Saclay
  • ,
  • B. Nawrot, Center for Molecular and Macromolecular Studies of the Polish Academy of Sciences
  • ,
  • N. J. Jones, University of Liverpool
  • ,
  • S. R. Paludan
  • S. Kossida, Universite de Montpellier
  • ,
  • C. Langevin, Universite Paris-Saclay
  • ,
  • N. Laguette, Universite de Montpellier

Inflammation is an essential part of immunity against pathogens and tumors but can promote disease if not tightly regulated. Self and non-self-nucleic acids can trigger inflammation, through recognition by the cyclic GMP-AMP (cGAMP) synthetase (cGAS) and subsequent activation of the stimulator of interferon genes (STING) protein. Here, we show that RNA:DNA hybrids can be detected by cGAS and that the Lysyl-tRNA synthetase (LysRS) inhibits STING activation through two complementary mechanisms. First, LysRS interacts with RNA:DNA hybrids, delaying recognition by cGAS and impeding cGAMP production. Second, RNA:DNA hybrids stimulate LysRS-dependent production of diadenosine tetraphosphate (Ap4A) that in turn attenuates STING-dependent signaling. We propose a model whereby these mechanisms cooperate to buffer STING activation. Consequently, modulation of the LysRS-Ap4A axis in vitro or in vivo interferes with inflammatory responses. Thus, altogether, we establish LysRS and Ap4A as pharmacological targets to control STING signaling and treat inflammatory diseases.

Original languageEnglish
JournalScience Advances
Volume6
Issue21
Pages (from-to)eaax3333
ISSN2375-2548
DOIs
Publication statusPublished - May 2020

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