The presence of DNA in the cytosol activates the type I interferon response of innate immunity. DNA is normally confined to the nucleus (and mitochondria), but in aberrant conditions such as infection, an increase in the abundance of DNA in the cytosol is detected by cyclic GMP–AMP synthase (cGAS), which triggers the innate immune response. Following disassembly of the nuclear envelope during mitosis, cGAS is recruited onto chromosomes and remains in the re-established nucleus, where it is kept inactive through binding to chromatin. The physiological relevance of nuclear cGAS remains unclear. Xu at al. now show that cGAS levels in the nucleus are also controlled through proteolysis.

An RNAi screen of ubiquitin–proteasome-associated genes implicated the cullin–RING E3 ligase 5 (CRL5) complex and its substrate receptor SPSB3 in degradation of nuclear cGAS. Indeed, depletion of SPSB3 or a CLR5 subunit, or treatment with the cullin–RING E3 ligases inhibitor MLN4924, blocked degradation of nuclear cGAS.