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  • Review Article
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Exploitation of the host ubiquitin system by human bacterial pathogens

Nature Reviews Microbiology volume 12, pages 399–413 (2014)Cite this article

Subjects

Key Points

  • Ubiquitylation is a host defence system that prevents bacterial infection; however, many bacterial pathogens exploit this system using virulence factors, such as secreted effector proteins and toxins.

  • In this Review, we highlight the strategies that human bacterial pathogens use to subvert and manipulate host defence systems by targeting ubiquitylation, with a focus on the role of molecular mimicry and secreted bacterial effector proteins.

  • A number of ubiquitin-like proteins (UBLs; such as SUMO and NEDD proteins), which have a similar sequence and three-dimensional structure to ubiquitin, also function as protein modifiers in eukaryotes. Bacteria have also evolved mechanisms to counteract these systems.

  • Our understanding of the mechanistic basis of bacterial interference with ubiquitylation in vitro has advanced, but our current knowledge of the interplay between pathogens (and their effectors) and host ubiquitin systems at the single-cell level and under in vivo conditions requires further study.

Abstract

Ubiquitylation is a crucial post-translational protein modification that regulates several cellular processes in eukaryotes, including inflammatory responses, endocytic trafficking and the cell cycle. Importantly, ubiquitylation also has a central role in modulating eukaryotic defence systems; however, accumulating evidence shows that many bacterial pathogens exploit host ubiquitin systems for their own benefit. In this Review, we highlight the ways in which human bacterial pathogens target ubiquitylation to subvert and manipulate host defence systems, with a focus on the role of molecular mimicry and secreted bacterial effector proteins. These strategies enable bacterial pathogens to maximize effector function and obtain nutrients, thereby promoting bacterial proliferation.

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Figure 1: The ubiquitylation cascade.
Figure 2: Bacterial interference with ubiquitin-mediated innate immune signalling.
Figure 3: Bacterial hijacking of ubiquitin-like systems.
Figure 4: Temporal and spatial regulation of ubiquitin pathways by bacterial pathogens.

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Acknowledgements

This work was supported by a Grant-in-Aid for Specially Promoted Research (grant number 23000012 to C.S), a Grant-in-Aid for Young Scientists (A) (grant number 23689027 to M.K), a Grant-in-Aid for Scientific Research on Innovative Areas (grant numbers 25121711 and 25112506 to M.K) and a Grant-in-Aid for Scientific Research (C) (grant number 25460527 to H.A). This work was also supported by research grants from the Yakult Bio-Science Foundation and the Nippon Institute for Biological Science, Japan.

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Authors and Affiliations

  1. Division of Bacterial Infection Biology, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108–8639, Japan

    Hiroshi Ashida, Minsoo Kim & Chihiro Sasakawa

  2. Nippon Institute for Biological Science, 9-2221-1 Shinmachi, Ome, Tokyo, 198–0024, Japan

    Chihiro Sasakawa

  3. Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260–8673, Japan

    Chihiro Sasakawa

Authors
  1. Hiroshi Ashida
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Correspondence to Hiroshi Ashida or Chihiro Sasakawa.

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PowerPoint slides

Glossary

Proteasome

A large complex of proteases that degrades ubiquitylated proteins in eukaryotic cells.

Phagolysosome

An organelle that is formed by the fusion of a phagosome and a lysosome. Within it, phagocytosed material is degraded by lysosomal hydrolytic enzymes.

Autophagosome

A double-membrane organelle that engulfs cellular components and delivers them to lysosomes.

Type III and type IV secretion systems

(T3SSs and T4SSs). Multicomponent machines that deliver bacterial effectors into host cells. T3SSs are evolutionarily and structurally related to flagellar export systems, whereas T4SSs are related to bacterial conjugation systems that translocate DNA.

Endocytosis

A process by which a cell imports molecules from the external environment by engulfing a volume of extracellular space within its membrane.

Reactive oxygen species

(ROS). Reactive chemical molecules that contain oxygen. They are generated by various cellular processes.

Pathogen-associated molecular patterns

(PAMPs). Pathogen-specific molecules, such as peptidoglycan, flagellin or viral RNA, that are sensed as foreign material by the innate immune system.

Prokaryotic ubiquitin-like protein system

(Pup system). A functional homologue of the eukaryotic ubiquitin system; it targets prokaryotic substrates for proteasomal degradation.

Attaching and effacing lesions

Lesions that form by intimate bacterial attachment, resulting in the effacement of the brush-border microvilli of epithelial cells and the formation of an actin pedestal on the cell surface.

Danger-associated molecular patterns

(DAMPs). Molecules that are released by damaged or stressed cells, either in the presence or absence of bacterial infection, and trigger immune responses.

Thioredoxin

(TRX). A small redox protein that is involved in several functions related to defence against oxidative stress and apoptosis.

TGFβ signalling

(Transforming growth factor β signalling). Members of the TGFβ family are cytokines that are involved in the regulation of cell proliferation, differentiation and apoptosis.

Papain-like hydrolytic fold

Certain hydrolytic enzymes have a Cys-His-Gln catalytic triad fold, which is conserved in papain cysteine protease.

Cyclomodulins

Bacterial effectors and toxins that inhibit eukaryotic cell cycle progression.

Actin stress fibre

Bundles that are composed of approximately 10–30 actin filaments; they have important roles in morphological stability, adhesion and motility.

Guanine nucleotide exchange factors

(GEFs). Proteins that activate GTPases by catalysing the conversion of the inactive GDP-bound form to the active GTP-bound form.

GTPase-activating proteins

(GAPs). Proteins that inactivate GTPases by catalysing the hydrolysis of GTP to GDP.

Vesicular membranes

Complex structures composed of a lipid bilayer that contains transmembrane proteins and encloses soluble hydrophilic components that are derived from the cytosol of a donor cell.

F-box domain

A 42–48 amino acid domain that is involved in polyubiquitylation in eukaryotic cells.

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Ashida, H., Kim, M. & Sasakawa, C. Exploitation of the host ubiquitin system by human bacterial pathogens. Nat Rev Microbiol 12, 399–413 (2014). https://doi.org/10.1038/nrmicro3259

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