Type I IFN expression is inhibited during cell division by CDK4/6

Abstract

SummaryCells are equipped to defend themselves from invading pathogens through sensors such as cGAS, which upon binding DNA induces type I interferon (IFN) expression. Whilst IFNs are crucial for limiting viral infection and activating adaptive immunity, uncontrolled production causes excessive inflammation and autoimmunity. cGAS binds DNA of both pathogenic and cellular origin and its activity is therefore tightly regulated. This is particularly apparent during mitosis, where cGAS association with chromatin following nuclear membrane dissolution and phosphorylation by mitotic kinases negatively regulate enzymatic activity. Here we describe a novel mechanism by which DNA sensing and other innate immune pathways are regulated during cell division, dependent on cyclin dependent kinases (CDK) 4 and 6. Inhibition of CDK4/6 using chemical inhibitors, shRNA-mediated depletion, or overexpression of cellular CDK4/6 inhibitor p16INK4a, greatly enhanced DNA- or cGAMP-induced expression of cytokines and IFN-stimulated genes (ISG). Mechanistically, CDK4/6-dependent inhibition mapped downstream of cytoplasmic signalling events including STING and IRF3 phosphorylation, limiting innate immune induction at the level of IFNβ mRNA expression. This regulation was universal, occurring in primary and transformed cells of human and murine origin, and broad, as IFNβ expression was inhibited in a CDK4/6-dependent manner downstream of multiple pattern recognition receptors. Together these findings demonstrate that host innate responses are limited by multiple mechanisms during cell division, thus defining cellular replication as an innate immune privileged process that may be necessary to avoid aberrant self-recognition and autoimmunity.