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Background   Salmonella  can invade host cells via a type three secretion system called T3SS-1 and its outer membrane proteins, PagN and Rck. However, the mechanism of PagN-dependent invasion pathway used by  Salmonella enterica , subspecies  enterica  serovar Typhimurium remains unclear.    Results  Here, we report that PagN is well conserved and widely distributed among the different species and subspecies of  Salmonella . We showed that PagN of  S.  Typhimurium was sufficient and necessary to enable non-invasive  E. coli  over-expressing PagN and PagN-coated beads to bind to and invade different non-phagocytic cells. According to the literature, PagN is likely to interact with heparan sulfate proteoglycan (HSPG) as PagN-mediated invasion could be inhibited by heparin treatment in a dose-dependent manner. This report shows that this interaction is not sufficient to allow the internalization mechanism. Investigation of the role of β1 integrin as co-receptor showed that mouse embryo fibroblasts genetically deficient in β1 integrin were less permissive to PagN-mediated internalization. Moreover, PagN-mediated internalization was fully inhibited in glycosylation-deficient pgsA-745 cells treated with anti-β1 integrin antibody, supporting the hypothesis that β1 integrin and HSPG cooperate to induce the PagN-mediated internalization mechanism. In addition, use of specific inhibitors and expression of dominant-negative derivatives demonstrated that tyrosine phosphorylation and class I phosphatidylinositol 3-kinase were crucial to trigger PagN-dependent internalization, as for the Rck internalization mechanism. Finally, scanning electron microscopy with infected cells showed microvillus-like extensions characteristic of Zipper-like structure, engulfing PagN-coated beads and  E. coli  expressing PagN, as observed during Rck-mediated internalization.    Conclusions  Our results supply new comprehensions into T3SS-1-independent invasion mechanisms of  S.  Typhimurium and highly indicate that PagN induces a phosphatidylinositol 3-kinase signaling pathway, leading to a Zipper-like entry mechanism as the  Salmonella  outer membrane protein Rck.

Investigation of the invasion mechanism mediated by the outer membrane protein PagN of Salmonella Typhimurium