STING signals to NF-κB from late endolysosomal compartments using IRF3 as an adaptor

Area of Science:

• Immunology
• Cellular Biology
• Molecular Biology

Background:

• Nuclear factor kappa B (NF-κB) is crucial for immune responses.
• The cGAS-STING pathway, activated by cytosolic DNA, induces type I interferons (IFNs) and NF-κB signaling, contributing to host defense and inflammation.
• The precise mechanism of STING-mediated NF-κB activation remains unclear.

Purpose of the Study:

• To elucidate the mechanism by which STING activates NF-κB.
• To identify key molecules and cellular compartments involved in STING-induced NF-κB signaling.
• To understand the temporal regulation of STING signaling to NF-κB.

Main Methods:

• Investigated STING-NF-κB activation dynamics using cell-based assays.
• Utilized biochemical methods to analyze protein-protein interactions, including IRF3 and TRAF6 recruitment to STING.
• Examined the role of cellular compartments, such as the Golgi and endolysosomes, in the signaling pathway.

Main Results:

• STING activates NF-κB in a delayed manner after relocating from the Golgi to endolysosomal compartments.
• NF-κB activation is dependent on the IFN-inducing transcription factor IRF3 but not on type I IFN signaling.
• IRF3 binds to STING at pS358, distinct from the pS366 site involved in IFN responses, facilitating TRAF6 recruitment and subsequent NF-κB activation.
• This signaling pathway is conserved across tetrapods.

Conclusions:

• STING utilizes a distinct signaling surface (pS358) and IRF3 as an adaptor to activate NF-κB via TRAF6 recruitment in endolysosomes.
• The temporal window between Golgi exit and lysosomal degradation is critical for STING-mediated NF-κB activation, potentially limiting inflammation.
• This study reveals a novel mechanism for STING-induced immune signaling and provides insights into inflammatory regulation.