Self-guarding of MORC3 enables virulence factor-triggered immunity

Pathogens employ virulence factors to inhibit the immune system(1). The guard hypothesis(2,3) postulates that hosts monitor (or ‘guard’) critical innate immune pathways such that their disruption by virulence factors provokes a secondary immune response(1). Here, we describe a ‘self-guarded’ immune pathway in human monocytes, in which guarding and guarded functions are united in one protein. We find that this pathway is triggered by ICP0, a key virulence factor of Herpes Simplex Virus-1 (HSV-1), resulting in robust induction of anti-viral type I interferon (IFN). Surprisingly, induction of IFN by ICP0 is independent of canonical immune pathways and the IRF3/7 transcription factors. A CRISPR-screen identified the ICP0-target MORC3(4) as an essential negative regulator of IFN. Loss of MORC3 recapitulates the IRF3/7-independent IFN response induced by ICP0. Mechanistically, ICP0 degrades MORC3, which leads to de-repression of a MORC3-regulated DNA element (MRE) adjacent to the IFNB1 locus. The MRE is required in cis for IFNB1 induction by the MORC3 pathway, but is not required for canonical IFN-inducing pathways. Besides repressing the MRE to regulate IFNB1, MORC3 is also a direct restriction factor of HSV-1(5). Our results thus suggest a model in which the primary anti-viral function of MORC3 is ‘self-guarded’ by its secondary IFN-repressing function: thus, a virus that degrades MORC3 to avoid its primary anti-viral function will unleash the secondary anti-viral IFN response.