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Article Dans Une Revue Science Advances Année : 2020

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

K. Polak
Armel Houel
  • Fonction : Auteur
  • PersonId : 1204929
Pierre Boudinot
Christelle Langevin

Résumé

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. Copyright
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Dates et versions

hal-02867466 , version 1 (05-11-2020)

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Paternité - Pas d'utilisation commerciale

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Jessica Guerra, A. L. Valadao, Dimitrios Vlachakis, K. Polak, I. K. Vila, et al.. Lysyl-tRNA synthetase produces diadenosine tetraphosphate to curb STING-dependent inflammation. Science Advances , 2020, 6 (21), pp.eaax3333. ⟨10.1126/sciadv.aax3333⟩. ⟨hal-02867466⟩
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