Self-guarding of MORC3 enables virulence factor-triggered immunity

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Pathogens employ virulence factors to suppress host immune responses.
• The guard hypothesis suggests hosts monitor immune pathways, triggering a secondary response upon disruption.
• A novel 'self-guarded' immune pathway combines monitoring and response functions within a single protein.

Purpose of the Study:

• To investigate a novel self-guarded immune pathway in human monocytes.
• To elucidate the mechanism by which herpes simplex virus type 1 (HSV-1) triggers antiviral responses.
• To identify host factors involved in regulating type I interferon (IFN) induction.

Main Methods:

• Utilized CRISPR screening to identify host factors regulating IFN induction.
• Investigated the role of MORC3 as a negative regulator of IFN.
• Analyzed the interaction between HSV-1 ICP0, MORC3, and the IFNB1 locus.

Main Results:

• HSV-1 ICP0 triggers a robust, canonical pathway-independent type I IFN response.
• MORC3 was identified as a crucial negative regulator of IFN induction.
• ICP0 degrades MORC3, leading to de-repression of a MORC3-regulated element (MRE) that induces IFNB1.

Conclusions:

• A self-guarded immune pathway exists where MORC3 restricts HSV-1 and represses IFNB1 induction.
• HSV-1 ICP0 degrades MORC3, releasing IFNB1 repression and activating a secondary antiviral response.
• This mechanism highlights a sophisticated interplay between viral virulence and host innate immunity.