Cyclic Di Nucleotides Trigger ULK1 (ATG1) Phosphorylation of STING to Prevent Sustained Innate Immune Signaling

By Hiroyasu Konno, K. Konno, G. Barber. Cell, 2013

626 citations recorded by the source corpus.

SUMMARY Activation of the STING (Stimulator of Interferon Genes) pathway by microbial or self-DNA, as well as cyclic di nucleotides (CDN), results in the induction of numerous genes that suppress pathogen replication and facilitate adaptive immunity. However, sustained gene transcription is rigidly prevented to avoid lethal STING-dependent pro-inflammatory disease by mechanisms that remain unknown. We demonstrate here that after autophagy-dependent STING delivery of TBK1 (TANK-binding kinase 1) to endosomal/lysosomal compartments and activation of transcription factors IRF3 (interferon regulatory factors 3) and NF-κB (nuclear factor kappa beta), that STING is subsequently phosphorylated by serine/threonine UNC-51-like kinase (ULK1/ATG1) and IRF3 function is suppressed. ULK1 activation occurred following disassociation from its repressor adenine monophosphate activated protein kinase (AMPK), and was elicited by CDN’s generated by the cGAMP synthase, cGAS. Thus, while CDN’s may initially facilitate STING function, they subsequently trigger negative-feedback control of STING activity, thus preventing the persistent transcription of innate immune genes.

Subfields: Immunology, Infectious Diseases, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1be0b67e3b10b53222e0bbd4b68f1e0a4e9a6b3c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Zhijian J. Chen
2. G. Barber
3. Tuo Li
4. T. Abe
5. G. Shadel
6. A. West
7. Y. Chiu
8. Xin Cai

In Infectious Diseases

1. Tuo Li
2. G. Barber
3. Xin Cai
4. Zhijian J. Chen
5. T. Abe

In Molecular Biology

1. Zhijian J. Chen
2. Tuo Li
3. T. Abe
4. R. Shaw
5. G. Barber
6. T. Gajewski
7. G. Shadel
8. Xin Cai

Citations in the corpus

• STING: infection, inflammation and cancer (2015, neutral): “Proteins intended for N-linked glycosylation and/or secretion are shunted through the TRAP complex into the luminal region of the ER following translation, although it is unknown whether STING is essential for any of these activities 17, 22 .”
• Innate Immune Pattern Recognition: A Cell Biological Perspective (2015, neutral): “This trafficking event relies on ATG9a and VPS34, suggesting that autophagy may play a role in the regulation of STING (241, 242).”
• Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates (2015, background): “Collectively, themajority of the candidate ULK1 phosphorylation sites we identified across these substrates contain hydrophobic residues in the 3 position (Figure 2F), consistent with our identified optimal ULK1 substrate sequence (Figure 1B) and with another site recently reported in another ULK1 s”
• The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. (2014, background): “Another study showed that cGAMP triggers the phosphorylation of STING by ULK1, a kinase of the autophagy pathway (Konno et al., 2013).”
• Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA (2014, background): “Similarly, activated STING is phosphorylated andmarked for lysosomal degradation (Konno et al., 2013).”
• Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation (2015, neutral): “Contrary to a previous report (25), the S365A mutation of mSTING also did not inhibit DNA-induced degradation of STING (fig.”
• Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity (2015, background): “This correlated with an increase in the apparent molecular weight of STING, which has been reported to be due to its phosphorylation (Konno et al., 2013).”
• Autophagy during viral infection — a double-edged sword (2018, background): “In addition, cGAMP leads to the dissociation of ULK1 from 5′-AMP-activated protein kinase catalytic subunit α2 (AMPK), and activated ULK1 then phosphorylates STING, leading to its degradation 26 (FIg.”
• Cytosolic-DNA-Mediated, STING-Dependent Proinflammatory Gene Induction Necessitates Canonical NF-κB Activation through TBK1 (2014, background): “However, STING was not observed to be phosphorylated by TBK1 in vitro (49).”