Alternative Endogenous Protein Processing via an Autophagy-Dependent Pathway Compensates for Yersinia-Mediated Inhibition of Endosomal Major Histocompatibility Complex Class II Antigen Presentation
2010 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 78, no 12, 5138-5150 p.Article in journal (Refereed) Published
Extracellular Yersinia pseudotuberculosis employs a type III secretion system (T3SS) for translocating virulence factors (Yersinia outer proteins, Yops) directly into the cytosol of eukaryotic cells. Recently, we used YopE as a carrier molecule for T3SS-dependent secretion and translocation of listeriolysin O (LLO) from Listeria monocytogenes. We demonstrated that translocation of chimeric YopE/LLO into the cytosol of macrophages by Yersinia results in the induction of a codominant antigen-specific CD4 and CD8 T-cell response in orally immunized mice. In this study, we addressed the requirements for processing and MHC class II presentation of chimeric YopE proteins translocated into the cytosol of macrophages by Yersinias T3SS. Our data demonstrate Yersinias ability to counteract exogenous MHC class II antigen presentation of secreted hybrid YopE by the action of wild-type YopE and YopH. In the absence of exogenous MHC class II antigen presentation, an alternative pathway was identified for YopE fusion proteins originating in the cytosol. This endogenous antigen processing pathway was sensitive to inhibitors of phagolysosomal acidification and macroautophagy, but it neither required the function of the proteasome nor of the TAP. Thus, by an autophagy-dependent mechanism, macrophages are able to compensate for the YopE/YopH-mediated inhibition of the endosomal MHC class II antigen presentation pathway for exogenous antigens. This is the first report demonstrating that autophagy might enable the host to mount an MHC class II-restricted CD4 T cell response against translocated bacterial virulence factors. We provide critical new insights into the interaction between the mammalian immune system and a human pathogen.
Place, publisher, year, edition, pages
American Society for Microbiology , 2010. Vol. 78, no 12, 5138-5150 p.
Microbiology in the medical area
IdentifiersURN: urn:nbn:se:umu:diva-43195DOI: 10.1128/IAI.00155-10ISI: 000284213600017PubMedID: 20876292OAI: oai:DiVA.org:umu-43195DiVA: diva2:412364