The IKK complex and TBK1/IKKε are recruited to STING through distinct mechanisms to activate NF-κB signaling.

STING activates NF-κB signaling through M1-linked ubiquitin-dependent recruitment of IKKγ and cooperation with TBK1/IKKε via its carboxyl-terminal tail in mammalian cells.

• Why it matters: Understanding how STING drives inflammation is crucial because its activation leads to inflammatory responses that can cause pathology, yet the molecular mechanisms remain poorly understood, hindering anti-inflammatory strategy development.
• What they did: The study identified that STING recruits IKKγ in an M1-linked ubiquitin-dependent manner to activate NF-κB and demonstrated that its carboxyl-terminal tail cooperates with IKKγ and the kinases TBK1/IKKε to promote pro-inflammatory gene expression in mammalian cells.
• The result: This work clarifies that M1-linked ubiquitin and the IKK complex are essential for STING-driven NF-κB activation and inflammatory gene expression, providing insights into inflammation regulation without IRF3 involvement.