IKKɛ induces STING non-IFN immune responses via a mechanism analogous to TBK1

Authors:

• Venkatraman, Rajan
• Balka, Katherine R.
• Wong, Wilson
• Sivamani, Jananipriya
• Magill, Zoe
• Tullett, Kirsteen M.
• Lane, Rachael M.
• Saunders, Tahnee L.
• Tailler, Maximilien
• Crack, Peter J.
• Wakim, Linda M.
• Lahoud, Mireille H.
• Lawlor, Kate E.
• Kile, Benjamin T.
• O’Keeffe, Meredith
• De Nardo, Dominic

Details:

iScience, Volume 27, Issue 9, 2024-09-20

Article Link: Click here

The cGAS-STING pathway responds to cytosolic DNA to elicit host immunity to infection. The activation of stimulator of interferon genes (STING) can trigger a number of critical cellular responses including inflammation, noncanonical autophagy, lipid metabolism, senescence, and cell death. STING-mediated immunity through the production of type I interferons (IFNs) and nuclear factor kappa B (NF-κB)-driven proinflammatory cytokines is primarily driven via the effector protein TBK1. We have previously found that IκBα kinase epsilon (IKKε), a homolog of TBK1, can also facilitate STING-NF-κB responses. Therefore, a thorough understanding of how IKKε participates in STING signaling is essential. Here, we used a combination of genetic and biochemical approaches to provide mechanistic details into how IKKε confers non-IFN (e.g., NF-κB and MAPK) STING responses in macrophages, including in the absence of TBK1. We demonstrate a conserved mechanism of STING binding between TBK1 and IKKε. These findings strengthen our understanding of cGAS-STING signaling and the preservation of host immunity in cases of TBK1-deficiency.