2 U-box domains

tion and subsequent proteolysis by the proteasome. Known targeted proteins degraded by the ubiquitination system of eukaryotic cells are cell cycle regulators, transcription factors, membrane proteins, and signal transduction components (Craig and Tyers 1999; Hershko and Ciechanover 1998). Furthermore, recently Perrin and colleagues (Perrin et al. 2004) reported that the ubiquitination system has a role in the recognition of bacterial pathogens in the cytosol of mammalian cells. In this scenario, cytosolic bacteria are tagged, by an unknown mechanism (i.e., either directly or indirectly), with polyubiquitin chains. In macrophages, ubi-quitin-tagged bacteria are recognized and degraded, with the proteasome having an indirect role. The intracellular bacterium S. typhimurium avoids this mechanism by staying in a membrane-surrounded compartment away from the ubiqui-tination machinery (Cossart and Sansonetti 2004), a mechanism which also holds good for Legionella. However, in addition Legionella seems to be able to modulate the eukaryotic ubiquitination machinery.

Further evidence for the adaptation of this pathogen during coevolution with eukaryotes may be the identification of proteins having homologues only in eukar-yotes. All three L. pneumophila genomes contain a sphingosine-1-phosphate lyase and two secreted apyrases, proteins never predicted in a prokaryotic proteome before (Table 15.2). These enzymes could be implicated in influencing the autop-hagy pathway, an immediate macrophage response to L. pneumophila (Amer and Swanson 2005). L.pneumophila initially avoids but subsequently tolerates its delivery to lysosomes by a process that resembles autophagy (Swanson and Fernandez-Moreira 2002). In eukaryotes sphingosine-1-phosphate lyase is thought to be a dual modulator of sphingosine-1-phosphate and ceramide metabolism. The level and the balance of both signaling molecules are important for inducing autophagy or apoptosis (Reiss et al. 2004). Apyrases have been isolated in autophagy vacuoles (Biederbick et al. 1999) and may influence the L. pneumophila phagosome by decreasing the concentration of NTPs and NDPs. In order to act in the eukaryotic cell these proteins should be secreted. This could be achieved by many different secretion systems present in L. pneumophila.

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