Met Receptor Tyrosine Kinase Degradation Is Altered in Response to the Leucine-rich Repeat of the Listeria Invasion Protein Internalin B

Entry of the bacterial pathogen Listeria monocytogenes into host epithelial cells is critical for infection and virulence. One major pathway for Listeria entry involves binding of the bacterial protein Internalin B to the host receptor tyrosine kinase Met (hepatocyte growth factor receptor). Activation of Met and downstream signaling cascades is critical for Listeria entry. Internalin B is composed of several structural domains including an N-terminal leucine-rich repeat that is sufficient for binding Met and stimulating downstream signal transduction. Internalin B is monomeric, whereas the leucine-rich repeat is dimeric when expressed as an isolated fragment. The different quaternary states of Internalin B and the leucine-rich repeat suggest that these two Met ligands might cause distinct biological effects. Here we demonstrate that Internalin B and the leucine-rich repeat fragment exhibit agonist properties that differentially influence Met down-regulation in lysosomes. Specifically, Met stability is increased in response to the leucine-rich repeat fragment compared with Internalin B. Interestingly, Internalin B and the leucine-rich repeat stimulate equivalent rates of clathrin-mediated Met internalization. However, the leucine-rich repeat is defective in promoting lysosomal down-regulation of Met and instead enhances receptor recycling to the cell surface. In addition, the leucine-rich repeat causes prolonged Met activation (phosphorylation) and increased cell motility compared with Internalin B. Taken together, our findings indicate that individual domains of Internalin B differentially regulate Met trafficking. The ability of the leucine-rich repeat fragment to promote Met recycling could account for the increased cell motility induced by this ligand. Entry of the bacterial pathogen Listeria monocytogenes into host epithelial cells is critical for infection and virulence. One major pathway for Listeria entry involves binding of the bacterial protein Internalin B to the host receptor tyrosine kinase Met (hepatocyte growth factor receptor). Activation of Met and downstream signaling cascades is critical for Listeria entry. Internalin B is composed of several structural domains including an N-terminal leucine-rich repeat that is sufficient for binding Met and stimulating downstream signal transduction. Internalin B is monomeric, whereas the leucine-rich repeat is dimeric when expressed as an isolated fragment. The different quaternary states of Internalin B and the leucine-rich repeat suggest that these two Met ligands might cause distinct biological effects. Here we demonstrate that Internalin B and the leucine-rich repeat fragment exhibit agonist properties that differentially influence Met down-regulation in lysosomes. Specifically, Met stability is increased in response to the leucine-rich repeat fragment compared with Internalin B. Interestingly, Internalin B and the leucine-rich repeat stimulate equivalent rates of clathrin-mediated Met internalization. However, the leucine-rich repeat is defective in promoting lysosomal down-regulation of Met and instead enhances receptor recycling to the cell surface. In addition, the leucine-rich repeat causes prolonged Met activation (phosphorylation) and increased cell motility compared with Internalin B. Taken together, our findings indicate that individual domains of Internalin B differentially regulate Met trafficking. The ability of the leucine-rich repeat fragment to promote Met recycling could account for the increased cell motility induced by this ligand. The Listeria monocytogenes surface protein Internalin B (InlB) 2The abbreviations used are: InlB, Internalin B; LRR, leucine-rich repeat; CHC, clathrin heavy chain; EEA1, early endosomal antigen; EGF, epidermal growth factor; HGF, hepatocyte growth factor; Met, hepatocyte growth factor receptor; LRR, leucine-rich repeat; MVB, multivesicular body; Tfn, transferrin; ANOVA, analysis of variance; MDCK, Madin-Darby canine kidney; WT, wild type; PBS, phosphate-buffered saline; FACS, fluorescence-activated cell sorter; siRNA, small Interfering RNA.2The abbreviations used are: InlB, Internalin B; LRR, leucine-rich repeat; CHC, clathrin heavy chain; EEA1, early endosomal antigen; EGF, epidermal growth factor; HGF, hepatocyte growth factor; Met, hepatocyte growth factor receptor; LRR, leucine-rich repeat; MVB, multivesicular body; Tfn, transferrin; ANOVA, analysis of variance; MDCK, Madin-Darby canine kidney; WT, wild type; PBS, phosphate-buffered saline; FACS, fluorescence-activated cell sorter; siRNA, small Interfering RNA. is a 630-amino acid protein critical for bacterial invasion into a broad range of host cells including endothelial cells, hepatocytes, and epithelial cell lines such as Vero and HeLa cells (1Dramsi S. 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The to and that of the in response to InlB and In cells the to that of that the in cell motility induced by cell we HeLa in HeLa cell motility in response to that induced by InlB, with our motility increased Met stability in response to with increased motility of HeLa and Here we a analysis of the Listeria protein our is that InlB and N-terminal fragment differentially regulate the of our indicate that in to InlB, Met and Met with increased cell The of Met is as InlB and rates of clathrin-mediated Met internalization. Met to the cell surface in response to suggest that in Met in to in the of InlB and with to receptor InlB and in in Met One is to the binding of InlB for In the of the growth receptor with the receptor receptor whereas growth the receptor the of early in receptor recycling to the cell surface R. R. 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