Eukaryotic-like Proteins in Legionella pneumophila: Modulation of Host Functions?

A major finding during the L. pneumophila genome analysis of strains Paris and Lens was the identification of a large number and a wide variety of proteins identified for the first time in a prokaryote, showing the strongest similarity to eukaryo-tic proteins or encoding motifs known to be implicated in protein-protein interac-

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tions, which are present only or primarily in eukaryotes. The presence of these proteins suggests that L. pneumophila has an important capacity to subvert host functions and to modulate them to its advantage. The identified proteins are predicted to be involved in all different stages of the Legionella life cycle, namely invasion, trafficking into the host cell, modulation of host cell functions, and evasion from the host cell.

The 31 proteins identified in strain Paris that exhibit the highest similarity to eukaryotic proteins are listed in Table 15.2. These proteins might fulfil important functions in L. pneumophila as they are conserved in all three sequenced genomes except two that are missing in strain Philadelphia 1 and three that are lacking in strain Lens (Table 15.2). More heterogeneity was found among the 30 proteins containing eukaryotic protein-protein interaction domains, in particular among the ankyrin repeat-containing proteins. There are 20 in strain Paris, 18 in strain Lens, and 16 in strain Philadelphia 1. Fourteen ankyrin proteins are shared by all three isolates (Table 15.3). Large families of ankyrin repeat proteins have so far been identified only in Coxiella burnetii (Seshadri et al. 2003) and Wolbachia pipi-tentis (Wu et al. 2004), two other intracellular bacteria. Ankyrin proteins are multifunctional proteins involved in many cellular pathways, so predicting the function of the Legionella ankyrin proteins is difficult. However, the fact that this protein family is that prominent in all three strains and in other intracellular pathogens suggests its importance for the intracellular life of Legionella. Ankyrin proteins may be involved in the interaction with the host cytoskeleton (Batrukova et al. 2000) or could be involved in targeting proteins to the plasma membrane or to the endoplasmic reticulum (Hryniewicz-Jankowska et al. 2002). They also may be components of transcriptional regulators and influence host gene expression (Caturegli et al. 2000).

The presence of proteins carrying F-box or U-box domains in the Legionella genomes is an intriguing finding, as it suggests that L. pneumophila is able to interfere with the ubiquitin machinery of eukaryotic cells. Two F-box proteins, one of which also contains an ankyrin domain, are present in all three sequenced strains. Strains Paris and Philadelphia 1 contain in addition each a third strain-specific F-box protein (Table 15.3). Strain Philadelphia 1 and Paris encode the only U-box protein identified in a prokaryotic genome to date. Interestingly, this protein is missing in strain Lens. Ubiquitination is a protein modification generally used by cells to tag proteins that are destined for proteasomal degradation. Ubiquitin is a highly conserved 76-amino-acid polypeptide that can be covalently attached to a lysine residue of the target protein by an E3-ubiquitin ligase, which is primarily responsible for providing substrate specificity to ubiquitin conjugation. Several classes of ubiquitin ligases have been described based on the presence of specific domains: HECT (homologous to E6-AP C terminus) domain, RING (really interesting new gene) finger, or the related PHD (pleckstrin homology domain) finger or U-box and the F-box domains (Hershko and Ciechanover 1998; Heyninck and Beyaert 2005). Thus the L. pneumophila U-box and F-box proteins might modulate the eukaryotic ubiquitination machinery. F-box proteins assembled into SCF ubi-quitin ligase complexes determine which substrate will be targeted for ubiquitina-

Tablel5.2 Proteins with the highest similarity score to eukaryotic proteins and their distribution in the three sequenced strains.

L. pneumophila Predicted product L. pneumophila L. pneumophila C-C Best hit BLASTp


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