Nicolas MANEL – Laboratory Innate Immunity, U932, Institut Curie, Paris, France

The ability to distinguish self vs non-self DNA is universal in life. In eukaryotes, the first paradigm relied on the notion that self DNA is compartmentalized within the nucleus and the mitochondria. In this model, the cytosol is generally devoid of DNA and cytosolic receptors recognize cytosolic DNA as non-self. This has led to the identification of cGAS and AIM2 as critical sensors of cytosolic DNA that activates innate immune responses. However, the nuclear envelope is a dynamic barrier: it breaks down in mitosis, and we and other have shown that it frequently ruptures in interphase in response to physiological conditions such as confined cell migration. Furthermore, DNA viruses and reverse-transcribing RNA viruses deliver their DNA into the nucleus, evoking the idea that self vs. non-self DNA discrimination should also occur within the nucleus.

In this talk, I will present our recent advances on this topic that suggest a new paradigm of self/non-self DNA recognition beyond intracellular compartmentalization.