Extracellular M. tuberculosis DNA Targets Bacteria for Autophagy by Activating the Host DNA-Sensing Pathway

By R. Watson, P. Manzanillo, J. Cox. Cell, 2012

703 citations recorded by the source corpus.

SUMMARY Eukaryotic cells sterilize the cytosol by using autophagy to route invading bacterial pathogens to the lysosome. During macrophage infection with Mycobacterium tuberculosis, a vacuolar pathogen, exogenous induction of autophagy can limit replication, but the mechanism of autophagy targeting and its role in natural infection remain unclear. Here we show that phagosomal permeabilization mediated by the bacterial ESX-1 secretion system allows cytosolic components of the ubiquitin-mediated autophagy pathway access to phagosomal M. tuberculosis. Recognition of extracelluar bacterial DNA by the STING-dependent cytosolic pathway is required for marking bacteria with ubiquitin, and delivery of bacilli to autophagosomes requires the ubiquitin-autophagy receptors p62 and NDP52 and the DNA-responsive kinase TBK1. Remarkably, mice with monocytes incapable of delivering bacilli to the autophagy pathway are extremely susceptible to infection. Our results reveal an unexpected link between DNA sensing, innate immunity, and autophagy and indicate a major role for this autophagy pathway in resistance to M. tuberculosis infection.

Subfields: Epidemiology, Immunology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/8e5c52c24fbecfa4b14e653a7cf983df48332fa3

How researchers see this paper

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

In Epidemiology

1. V. Deretic
2. P. Codogno
3. Zhijian J. Chen
4. P. Boya
5. F. Reggiori
6. Beth Levine
7. D. Klionsky
8. N. Mizushima

In Immunology

1. A. Ablasser
2. Zhijian J. Chen
3. V. Deretic
4. G. Weiss
5. U. Schaible
6. Shizuo Akira
7. N. Perkins
8. Tuo Li

In Public Health, Environmental and Occupational Health

1. Zhijian J. Chen
2. P. Boya
3. P. Codogno
4. V. Deretic
5. G. Hotamışlıgil

Citations in the corpus

• STING: infection, inflammation and cancer (2015, neutral): “[50] [51] [52] [53] [54] [55] .”
• Immune sensing of DNA (2013, neutral): “Beyond IFN induction, the DNA-sensing signaling machinery has been reported to stimulate autophagy during M. tuberculosis infection, which was essential for optimal antimicrobial defense and was dependent on STING and TBK1 (Rasmussen et al., 2011; Watson et al., 2012).”
• cGAS in action: Expanding roles in immunity and inflammation (2019, background): “to mobilize autophagy to resist Mycobacterium tuberculosis infection (32).”
• Autophagy in inflammation, infection, and immunometabolism (2021, background): “Increased lung inflammation is observed in Mtb-infected mice with defective Atg5 in the myeloid lineage (Castillo et al., 2012; Kimmey et al., 2015; Watson et al., 2012) and whole-body Smurf1−/− mice (Franco et al.”
• Emerging regulation and functions of autophagy (2013, background): “Those include the Pink1 kinase, the Parkin ligase and the mitochondrial outer membrane protein FUNDC (all of which were linked to mitophagy [20] [21] [22] , and the SMURF1 ligase and the STING adaptor, which participate in the clearance of pathogens 23, 24 .”
• Macrophage defense mechanisms against intracellular bacteria (2015, background): “In the cytoplasm, NOD1, NOD2, and Galectin 3 sense DAP, muramyl-dipeptide, and b-galactosides, respectively, while STING is the recently described receptor for cyclic GMP-AMP generated from microbial DNA, which is delivered into the cytoplasm by cGAMP synthase, which triggers type 1 interferon produ”