Extracellular M. Tuberculosis DNA Targets Bacteria for Autophagy by Activating the Host DNA-sensing Pathway

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 Aug 21

PMID 22901810

Citations 440

Authors

Robert O Watson

Paolo S Manzanillo

Jeffery S Cox

Affiliations

Soon will be listed here.

Abstract

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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References

Saitoh T, Fujita N, Jang M, Uematsu S, Yang B, Satoh T . Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 2008; 456(7219):264-8. DOI: 10.1038/nature07383. View

Youle R, Narendra D . Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2010; 12(1):9-14. PMC: 4780047. DOI: 10.1038/nrm3028. View

Kumar D, Nath L, Kamal M, Varshney A, Jain A, Singh S . Genome-wide analysis of the host intracellular network that regulates survival of Mycobacterium tuberculosis. Cell. 2010; 140(5):731-43. DOI: 10.1016/j.cell.2010.02.012. View

Nakahira K, Haspel J, Rathinam V, Lee S, Dolinay T, Lam H . Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2010; 12(3):222-30. PMC: 3079381. DOI: 10.1038/ni.1980. View

Armstrong J, HART P . Response of cultured macrophages to Mycobacterium tuberculosis, with observations on fusion of lysosomes with phagosomes. J Exp Med. 1971; 134(3 Pt 1):713-40. PMC: 2139093. DOI: 10.1084/jem.134.3.713. View

Py B, Lipinski M, Yuan J . Autophagy limits Listeria monocytogenes intracellular growth in the early phase of primary infection. Autophagy. 2007; 3(2):117-25. DOI: 10.4161/auto.3618. View

Whitchurch C, Tolker-Nielsen T, Ragas P, Mattick J . Extracellular DNA required for bacterial biofilm formation. Science. 2002; 295(5559):1487. DOI: 10.1126/science.295.5559.1487. View

Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey D . AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009; 458(7237):514-8. PMC: 2726264. DOI: 10.1038/nature07725. View

Yoshikawa Y, Ogawa M, Hain T, Yoshida M, Fukumatsu M, Kim M . Listeria monocytogenes ActA-mediated escape from autophagic recognition. Nat Cell Biol. 2009; 11(10):1233-40. DOI: 10.1038/ncb1967. View

10.

Cemma M, Kim P, Brumell J . The ubiquitin-binding adaptor proteins p62/SQSTM1 and NDP52 are recruited independently to bacteria-associated microdomains to target Salmonella to the autophagy pathway. Autophagy. 2010; 7(3):341-5. PMC: 3060414. DOI: 10.4161/auto.7.3.14046. View

11.

Deretic V, Levine B . Autophagy, immunity, and microbial adaptations. Cell Host Microbe. 2009; 5(6):527-49. PMC: 2720763. DOI: 10.1016/j.chom.2009.05.016. View

12.

Hagstrom J, Ludtke J, Bassik M, Sebestyen M, Adam S, Wolff J . Nuclear import of DNA in digitonin-permeabilized cells. J Cell Sci. 1997; 110 ( Pt 18):2323-31. DOI: 10.1242/jcs.110.18.2323. View

13.

Kirkin V, Lamark T, Sou Y, Bjorkoy G, Nunn J, Bruun J . A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol Cell. 2009; 33(4):505-16. DOI: 10.1016/j.molcel.2009.01.020. View

14.

MacMicking J, Taylor G, McKinney J . Immune control of tuberculosis by IFN-gamma-inducible LRG-47. Science. 2003; 302(5645):654-9. DOI: 10.1126/science.1088063. View

15.

Ryzhakov G, Randow F . SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANK. EMBO J. 2007; 26(13):3180-90. PMC: 1914091. DOI: 10.1038/sj.emboj.7601743. View

16.

Stetson D, Medzhitov R . Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity. 2006; 24(1):93-103. DOI: 10.1016/j.immuni.2005.12.003. View

17.

Schaible U, Russell D . Mycobacterium-containing phagosomes are accessible to early endosomes and reflect a transitional state in normal phagosome biogenesis. EMBO J. 1996; 15(24):6960-8. PMC: 452522. View

18.

Pym A, Brodin P, Majlessi L, Brosch R, Demangel C, Williams A . Recombinant BCG exporting ESAT-6 confers enhanced protection against tuberculosis. Nat Med. 2003; 9(5):533-9. DOI: 10.1038/nm859. View

19.

Takeuchi O, Akira S . Pattern recognition receptors and inflammation. Cell. 2010; 140(6):805-20. DOI: 10.1016/j.cell.2010.01.022. View

20.

Zheng Y, Shahnazari S, Brech A, Lamark T, Johansen T, Brumell J . The adaptor protein p62/SQSTM1 targets invading bacteria to the autophagy pathway. J Immunol. 2009; 183(9):5909-16. DOI: 10.4049/jimmunol.0900441. View