Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Dec 5:7:487.
doi: 10.3389/fcimb.2017.00487. eCollection 2017.

Hijacking of the Host Ubiquitin Network by Legionella pneumophila

Jiazhang Qiu  1   2 , Zhao-Qing Luo  1   2   3
Affiliations
Review

Hijacking of the Host Ubiquitin Network by Legionella pneumophila

Jiazhang Qiu et al. Front Cell Infect Microbiol. .

Abstract

Protein ubiquitination is critical for regulation of numerous eukaryotic cellular processes such as protein homeostasis, cell cycle progression, immune response, DNA repair, and vesicular trafficking. Ubiquitination often leads to the alteration of protein stability, subcellular localization, or interaction with other proteins. Given the importance of ubiquitination in the regulation of host immunity, it is not surprising that many infectious agents have evolved strategies to interfere with the ubiquitination network with sophisticated mechanisms such as functional mimicry. The facultative intracellular pathogen Legionella pneumophila is the causative agent of Legionnaires' disease. L. pneumophila is phagocytosed by macrophages and is able to replicate within a niche called Legionella-containing vacuole (LCV). The biogenesis of LCV is dependent upon the Dot/Icm type IV secretion system which delivers more than 330 effector proteins into host cytosol. The optimal intracellular replication of L. pneumophila requires the host ubiquitin-proteasome system. Furthermore, membranes of the bacterial phagosome are enriched with ubiquitinated proteins in a way that requires its Dot/Icm type IV secretion system, suggesting the involvement of effectors in the manipulation of the host ubiquitination machinery. Here we summarize recent advances in our understanding of mechanisms exploited by L. pneumophila effector proteins to hijack the host ubiquitination pathway.

Keywords: bacterial virulence; cell signaling; effectors; posttranslational modification; type IV secretion.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Enzymes and chemical reactions involved in ubiquitination catalyzed by the canonical mechanism and by members of the SidE family proteins. (A) In the canonical mechanism, a ubiquitin molecule is activated by E1 at the expense of an ATP. The activated ubiquitin is first linked to E1 via a labile thioester bond prior to being transferred to the E2 conjugation enzyme, also linked by a thioester bond. The final step of the reaction differs greatly among different groups of E3 enzymes which dictate substrate specificity. For members of the HECT family of E3 enzymes (left), a reaction intermediate is formed, again by the formation of a thiolester bond between ubiquitin and E3, from where it is finally linked to lysine residues of the substrate. For other groups of E3 enzymes such as the RING family, the ubiquitin moiety is directly transferred to the substrate without the formation of an intermediate. (B) The reaction catalyzed by the SidE family begins with ubiquitin activation by ADP-ribosylation at Arg42 to produce the reaction intermediate ADP-ribosylated ubiquitin (ADPR-Ub), a nicotinamide moiety is released in this step of the reaction. In the second reaction, ADPR-Ub is cleaved by a phosphodiesterase (PDE) activity also embedded in these proteins, resulting in the attachment of phosphoribosylated ubiquitin to serine residues of the substrate and the release of AMP. How ubiquitin is recognized by the mART motif is unknown, nor is the mechanism of substrate recognition presumably by the PDE domain.
Figure 2
Figure 2
Temporal regulation of effector activity by effectors. (A) Regulation of SidH by LubX. The expression of lubX does not become apparent until after several hours postinfection. This ubiquitin E3 ligase functions with the host machinery to ubiquitinate SidH, resulting its degradation by the proteasome. (B) Regulation of SidEs by SidJ. SidEs catalyze the ubiquitination of RTN4 or ER-associated Rab small GTPases such as Rab33b whereas SidJ reverses such modification by its phosphodiesterase activity. In the early phase of infection, the ratio between translocated SidEs and SidJ favors ubiquitination of relevant substrates, which is beneficial for the biogenesis of the LCV. Several hours after bacterial uptake, the activity of SidJ becomes dominant due to higher amount of translocated protein, which reverses the ubiquitination imposed by the SidEs.
Figure 3
Figure 3
A diagram of the dual biochemical activities of SidJ. (A) Cleavage of phosphodiester bond by SidJ. SidJ specifically recognizes the phophosdiester bond that links phosphoribosylated ubiquitin to serine residue on the substrate. This activity allows the substrate to return to its unmodified form; it also produces phosphoribosylated ubiquitin, which may be further hydrolyzed by enzymes from either the host or the bacterium or both. (B) Cleavage of isopeptide bond by SidJ. SidJ recognizes and cleaves the isopeptide bond that links ubiquitin to lysine residue of the substrate or another ubiquitin moiety. This activity produces free ubiquitin. Since mutants that retain only one of these two activities have not been isolated, the importance of the classical DUB activity of SidJ is not clear.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Al-Khodor S., Price C. T., Habyarimana F., Kalia A., Abu Kwaik Y. (2008). A Dot/Icm-translocated ankyrin protein of Legionella pneumophila is required for intracellular proliferation within human macrophages and protozoa. Mol. Microbiol. 70, 908–923. 10.1111/j.1365-2958.2008.06453.x - DOI - PMC - PubMed
    1. Ashida H., Kim M., Sasakawa C. (2014). Exploitation of the host ubiquitin system by human bacterial pathogens. Nat. Rev. Microbiol. 12, 399–413. 10.1038/nrmicro3259 - DOI - PubMed
    1. Bardill J. P., Miller J. L., Vogel J. P. (2005). IcmS-dependent translocation of SdeA into macrophages by the Legionella pneumophila type IV secretion system. Mol. Microbiol. 56, 90–103. 10.1111/j.1365-2958.2005.04539.x - DOI - PubMed
    1. Bhogaraju S., Dikic I. (2016). Cell biology: ubiquitination without E1 and E2 enzymes. Nature 533, 43–44. 10.1038/nature17888 - DOI - PubMed
    1. Bhogaraju S., Kalayil S., Liu Y. B., Bonn F., Colby T., Matic I., et al. . (2016). Phosphoribosylation of ubiquitin promotes serine ubiquitination and impairs conventional ubiquitination. Cell 167, 1636.e13–1649.e13. 10.1016/j.cell.2016.11.019 - DOI - PubMed

Publication types