| Title: |
AMPK regulates innate immune signaling and viral control through ULK-1 dependent decrease of STING expression (INM7P.430) |
| Authors: |
Prantner, Daniel; Perkins, Darren; Vogel, Stefanie |
| Source: |
The Journal of Immunology ; volume 192, issue Supplement_1, page 123.8-123.8 ; ISSN 0022-1767 1550-6606 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2014 |
| Description: |
The host protein STING has been shown to be essential for recognition of both viral and intracellular bacterial pathogens, but its regulation remains unclear. Previously, we have described how mitochondrial membrane potential regulates STING-dependent IFN-β induction. The kinase activity of AMPK is controlled by cellular metabolism and intracellular calcium concentration. The goal of our study was to examine whether STING-dependent signaling is regulated by AMPK. Addition of an intracellular calcium chelator or an AMPK inhibitor suppressed IFN-β induction in mouse macrophages stimulated with the STING-dependent ligand DMXAA. Similarly, mouse embryonic fibroblasts (MEFS) lacking AMPK alpha failed to up-regulate IFN-β after DMXAA treatment. Additionally, these AMPK-/- MEFS failed to activate the IRF3-kinase TBK-1 and phosphorylate the transcription factor IRF3 after DMXAA treatment, confirming that STING-dependent signaling is AMPK-dependent. Loss of AMPK led to constitutive activation of the known STING negative regulator ULK-1 and a decrease in the basal level of STING protein. As a result, AMPK-/- MEFS exhibit impaired control of Vesicular Stomatitis Virus, a virus sensed by STING. ULK-1 has been shown to phosphorylate and degrade STING in the presence of dsDNA through the sensor protein cGAS. But in WT MEFS, STING was degraded in response to DMXAA in a cGAS- and ULK-1- independent manner, illustrating a novel regulatory pathway for this crucial signaling protein. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.4049/jimmunol.192.supp.123.8 |
| Availability: |
https://doi.org/10.4049/jimmunol.192.supp.123.8; https://academic.oup.com/jimmunol/article/192/Supplement_1/123.8/7992176 |
| Rights: |
https://academic.oup.com/pages/standard-publication-reuse-rights |
| Accession Number: |
edsbas.41A6A1F1 |
| Database: |
BASE |