TLR2 and RIP2 Pathways Mediate Autophagy of Listeria monocytogenes via Extracellular Signal-regulated Kinase (ERK) Activation

• Published in: The Journal of biological chemistry 2011-12, Vol.286 (50), p.42981-42991
• Main Authors: Anand, Paras K., Tait, Stephen W.G., Lamkanfi, Mohamed, Amer, Amal O., Nunez, Gabriel, Pagès, Gilles, Pouysségur, Jacques, McGargill, Maureen A., Green, Douglas R., Kanneganti, Thirumala-Devi
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; Autophagy - immunology; Blotting, Western; Cell Line; Cells, Cultured; Development Biology; ERK; Extracellular Signal-Regulated MAP Kinases; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Immunology; Life Sciences; Listeria monocytogenes; Listeria monocytogenes - immunology; Listeria monocytogenes - pathogenicity; Listeriosis; Listeriosis - immunology; Macrophages; Macrophages - cytology; Macrophages - immunology; Mice; Mice, Mutant Strains; Microscopy, Electron, Transmission; Nod-like receptors (NLR); Nod2 Signaling Adaptor Protein; Nod2 Signaling Adaptor Protein - genetics; Nod2 Signaling Adaptor Protein - metabolism; Receptor-Interacting Protein Serine-Threonine Kinase 2; Receptor-Interacting Protein Serine-Threonine Kinases; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Signal Transduction; Signal Transduction - genetics; Toll-Like Receptor 2; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism; Toll-like receptors (TLR)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.310599

Listeria monocytogenes is a facultative intracellular pathogen that invades both phagocytic and non-phagocytic cells. Recent studies have shown that L. monocytogenes infection activates the autophagy pathway. However, the innate immune receptors involved and the downstream signaling pathways remain unknown. Here, we show that macrophages deficient in the TLR2 and NOD/RIP2 pathway display defective autophagy induction in response to L. monocytogenes. Inefficient autophagy in Tlr2−/− and Nod2−/− macrophages led to a defect in bacteria colocalization with the autophagosomal marker GFP-LC3. Consequently, macrophages lacking TLR2 and NOD2 were found to be more susceptible to L. monocytogenes infection, as were the Rip2−/− mice. Tlr2−/− and Nod2−/− cells showed perturbed NF-κB and ERK signaling. However, autophagy against L. monocytogenes was dependent selectively on the ERK pathway. In agreement, wild-type cells treated with a pharmacological inhibitor of ERK or ERK-deficient cells displayed inefficient autophagy activation in response to L. monocytogenes. Accordingly, fewer bacteria were targeted to the autophagosomes and, consequently, higher bacterial growth was observed in cells deficient in the ERK signaling pathway. These findings thus demonstrate that TLR2 and NOD proteins, acting via the downstream ERK pathway, are crucial to autophagy activation and provide a mechanistic link between innate immune receptors and induction of autophagy against cytoplasm-invading microbes, such as L. monocytogenes. Background:Listeria monocytogenes is an intracellular pathogen that invades the host cytoplasm. Results: Cells deficient in TLR2 and NOD2 show defective autophagy of Listeria monocytogenes. Conclusion: Autophagy of Listeria is dependent on ERK pathway that is perturbed in TLR2- and NOD2-deficient cells. Significance: Our study establishes the role of innate immune receptors in autophagy of intracellular pathogens.