Skip to main content

Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner.

The Journal of experimental medicine

Authors: Tina Schumann, Santiago Costas Ramon, Nadja Schubert, Mohamad Aref Mayo, Melanie Hega, Katharina Isabell Maser, Servi-Remzi Ada, Lukas Sydow, Mona Hajikazemi, Markus Badstübner, Patrick Müller, Yan Ge, Farhad Shakeri, Andreas Buness, Benjamin Rupf, Stefan Lienenklaus, Barbara Utess, Lina Muhandes, Michael Haase, Luise Rupp, Marc Schmitz, Thomas Gramberg, Nicolas Manel, Gunther Hartmann, Thomas Zillinger, Hiroki Kato, Stefan Bauer, Alexander Gerbaulet, Katrin Paeschke, Axel Roers, Rayk Behrendt

Defects in nucleic acid metabolizing enzymes can lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing type I interferon-driven inflammatory diseases. In these pathophysiological conditions, activation of the DNA sensor cGAS and IFN production are linked to spontaneous DNA damage. Physiological, or tonic, IFN signaling on the other hand is essential to functionally prime nucleic acid sensing pathways. Here, we show that low-level chronic DNA damage in mice lacking the Aicardi-Goutières syndrome gene SAMHD1 reduced tumor-free survival when crossed to a p53-deficient, but not to a DNA mismatch repair-deficient background. Increased DNA damage did not result in higher levels of type I interferon. Instead, we found that the chronic interferon response in SAMHD1-deficient mice was driven by the MDA5/MAVS pathway but required functional priming through the cGAS/STING pathway. Our work positions cGAS/STING upstream of tonic IFN signaling in Samhd1-deficient mice and highlights an important role of the pathway in physiological and pathophysiological innate immune priming.

© 2022 Schumann et al.

PMID: 36346347

Participating cluster members