Extracellular M. tuberculosis DNA Targets Bacteria for Autophagy by Activating the Host DNA-Sensing Pathway
Open accessAbstract
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.
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TLR4-NF-κB signaling induces selective autophagy after pathogen invasion.
“TLR4-NF-κB signaling was previously shown to induce selective autophagy after pathogen invasion52–54.”
From Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration (2020) · cites this paper as [53]
In Results, under “Cytosolic DNA Sensing Mediates Targeting of M. tuberculosis to Autophagosomes” (page unavailable), the paper reports that autophagy targeting remained normal in macrophages deficient in TLR signaling. It instead identifies cytosolic DNA sensing through STING as necessary for selective targeting of M. tuberculosis; it does not show induction by TLR4–NF-κB signaling. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredSTING is the receptor for cyclic GMP-AMP generated from microbial DNA, which is delivered into the cytoplasm by cGAMP synthase and triggers type 1 interferon production.
“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 production (1, 2).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [1]
A similar sequence of events occurs upon infection of macrophages with M. tuberculosis, after STING1-dependent recognition of extracellular DNA and subsequent recruitment of SQSTM1/p62, CALCOCO2, and TBK1.
“A similar sequence of events occurs upon infection of macrophages with M. tuberculosis, after the STING1‐dependent recognition of extracellular DNA (Watson et al, 2012) and the subsequent recruitment of SQSTM1/p62, CALCOCO2, and TBK1 (Pilli et al, 2012).”
From Autophagy in major human diseases (2021) · cites this paper as Watson et al, 2012
The autophagosome-generating machinery perceives intracellular microbes of bacterial origin as a substrate, triggering xenophagy, which has been typified for infections mediated by Salmonella enterica serovar Typhimurium or Mycobacterium tuberculosis.
“From a mere cell autonomous standpoint, the autophagosome‐generating machinery perceives intracellular microbes of bacterial origin (especially those escaping their membranes of internalization) as a substrate, thereby triggering a selective form of autophagy known as “xenophagy”, which has been extensively typified for infections mediated by Salmonella enterica serovar Typhimurium (Birmingham et”
From Autophagy in major human diseases (2021) · cites this paper as Watson et al, 2012
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- Authors
- Watson, R. O., Manzanillo, P. S., & Cox, J. S.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Cox, Jeffery S.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 150
- Issue
- 4
- Pages
- 803-815
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3708656
- OpenAlex
- W2097481253
- Cited by
- 755
- References
- 67
- Citations by year
- 2026: 27 · 2025: 31 · 2024: 43 · 2023: 44 · 2022: 57 · 2021: 64 · 2020: 55 · 2019: 55 · 2018: 62 · 2017: 67 · 2016: 67 · 2015: 63 · 2014: 64 · 2013: 47 · 2012: 9
- FWCI
- 40.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R01AI081727, P01AI063302)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- Mycobacterium tuberculosis, autophagy, STING, DNA sensing, ESX-1 secretion system, p62, NDP52, TBK1, monocytes, innate immunity, macrophage infection
- MeSH terms
- Autophagy-Related Protein 5, STING Protein, Animals, Autophagy, Cytosol, Deoxyribonucleases, DNA, Bacterial, Immunity, Innate, Lysosomes, Macrophages, Membrane Proteins, Microtubule-Associated Proteins, Mycobacterium tuberculosis, Phagosomes, Ubiquitin, Mice, Ubiquitination
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