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β₁ Integrin-Dependent Engulfment of Yersinia enterocolitica by Macrophages Is Coupled to the Activation of Autophagy and Suppressed by Type III Protein Secretion¹

Anne Deuretzbacher,^* Nicole Czymmeck,^* Rudolph Reimer, Konrad Trülzsch, Kristin Gaus,^* Heinrich Hohenberg, Jürgen Heesemann, Martin Aepfelbacher,^* and Klaus Ruckdeschel^2*

^*Institute for Medical Microbiology, Virology, and Hygiene, University Medical Center Eppendorf, Hamburg, Germany; Heinrich-Pette-Institute for Experimental Virology and Immunology, University of Hamburg, Hamburg, Germany; and Max von Pettenkofer-Institute for Hygiene and Medical Microbiology, Munich, Germany

Autophagy is a central lysosomal degradation process that is essential for the maintenance of cellular homeostasis. Autophagy has furthermore emerged as integral part of the host immune response. Autophagic processes promote the separation and degradation of intracellular microorganisms which contributes to the development of innate and adaptive immunity. Some pathogenic microbes have therefore evolved mechanisms to evade or impede autophagy. We analyzed the effects of the enteropathogenic bacterium Yersinia enterocolitica on autophagy in macrophages. Yersiniae use a number of defined adhesins and secreted proteins to manipulate host immune responses. Our results showed that Y. enterocolitica defective in type III protein secretion efficiently activated autophagy in macrophages. Autophagy was mediated by the Yersinia adhesins invasin and YadA and particularly depended on the engagement of β₁ integrin receptors. Several autophagy-related events followed β₁ integrin-mediated engulfment of the bacteria including the formation of autophagosomes, processing of the marker protein LC3, redistribution of GFP-LC3 to bacteria-containing vacuoles, and the segregation of intracellular bacteria by autophagosomal compartments. These results provide direct evidence for the linkage of β₁ integrin-mediated phagocytosis and autophagy induction. Multiple microbes signal through integrin receptors, and our results suggest a general principle by which the sensing of an extracellular microbe triggers autophagy. Owing to the importance of autophagy as host defense response, wild-type Y. enterocolitica suppressed autophagy by mobilizing type III protein secretion. The subversion of autophagy may be part of the Y. enterocolitica virulence strategy that supports bacterial survival when β₁ integrin-dependent internalization and autophagy activation by macrophages are deleterious for the pathogen.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Deutsche Forschungsgemeinschaft Grants DFG Ru788/1 and 3.

² Address correspondence and reprint requests to Dr. Klaus Ruckdeschel, Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. E-mail address: k.ruckdeschel{at}uke.uni-hamburg.de

³ Abbreviations used in this paper: Atg, autophagy-related protein; HEK, human embryonic kidney; LC3, light chain protein 3; 3-MA, 3-methyladenine; TEM, transmission electron microscopy; YadA, Yersinia adhesin A; Yops, Yersinia outer proteins.