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Targeting of host-cell ubiquitin and ubiquitin-like pathways by bacterial factors

Nature Reviews Microbiology volume 2, pages 779–788 (2004)Cite this article

Key Points

  • This article reviews the relationship between bacteria and host ubiquitin and ubiquitin-like pathways (ULPs). Bacterial virulence factors can mimic the regulatory activities of ULPs and can also interfere with cellular protein sensitivity to ULPs. Due to their sensitivity to ULPs, virulence factors can also modulate their own half-life and localization within the host cell.

  • The Yersinia protein YopJ directly interferes with the ubiquitin-like cellular machinery. YopJ contains a SUMO1 ubiquitin-like protease activity, which might account for its pleiotropic inhibitory effects on cell signalling pathways.

  • Agrobacterium tumefaciens, the causative agent of crown-gall tumours, secretes (via a type IV secretion mechanism) the virulence factor VirF, which is a protein that interacts with homologues of the yeast SKP1 subunit of the SCF complex.

  • Proteasome inhibitors confer macrophage resistance to the lethal factor (LF) toxin of Bacillus anthracis. These inhibitors also confer macrophage resistance to sublethal doses of LF by a phenomenon known as toxin-induced resistance (TIR). TIR cells maintain a steady level of ubiquitylated proteins on cell intoxication.

  • The uropathogenic Escherichia coli (UPEC) toxin CNF1 catalyses the permanent activation of Rho GTPases, which is followed by their ubiquitin-mediated proteasomal degradation. The mechanism of action of this toxin results in efficient UPEC internalization into host cells, intercellular junction disruption and induction of epithelial cell migration.

  • Salmonella injects (via type III secretion) two virulence factors that result in Rac and Cdc42 activation (SopE) and inhibition (SptP). The increased sensitivity of SopE to ubiquitin-mediated proteasomal degradation results in the transient nature of Rac and Cdc42 activation and a reduced inflammatory response.

  • Lumenal prokaryotic microflora actively establish an interaction with host ULPs to limit epithelial inflammatory responses. Inhibition of these inflammatory response is achieved by preventing proteasomal degradation of IκB through the specific inhibition of its ubiquitylati

Abstract

Evidence has emerged that pathogenic or commensal bacteria subvert the ubiquitin and ubiquitin-like pathways (ULPs) during interaction with their hosts. This finding is consistent with ULPs being important in signalling cascades that relay the cellular recognition of pathogens to trigger a genetic response by the host. Subversion of these pathways also contributes to the prevention of host-cell damage by limiting the intracellular activities of bacterial virulence factors. Given the growing implication of ULPs in cell signalling, autophagy and membrane trafficking, there is little doubt that further examples of direct or indirect interactions between bacterial factors and ULPs will be documented.

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Figure 1: The ubiquitin-transfer reaction and targeting to the proteasome.
Figure 2: Involvement of ULPs in Toll-like receptor activity.
Figure 3: Interaction of bacterial factors with host ubiquitin-like pathways.
Figure 4: Transient activation of Rac by CNF1 toxin and the SopE virulence factor.

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Acknowledgements

We are grateful to P. Boquet for fruitful discussions and advice during the writing of the manuscript. We thank P. Munro and M. M. Mhlanga for critical reading of the manuscript. We apologize to those colleagues whose important contributions could not be cited owing to space restrictions. Our laboratory is supported by funding from the Institut National de la Santé et de la Recherche Médicale (INSERM), and by grants from the Association pour la Recherche sur le Cancer and the Ligue Nationale Contre le Cancer.

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  1. Institut National de la Santé et de la Recherche Médicale (INSERM), U627, Faculté de Médecine, 28 Avenue de Valombrose, Nice, 06107 Cedex 2, France

    Laurent Boyer & Emmanuel Lemichez

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  1. Laurent Boyer
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Correspondence to Emmanuel Lemichez.

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DATABASES

SwissProt

Cdc42

CUL1

IL8

MCP1

MEK1

MEK2

MKK6

NEDD8

ROC1

SKP1

SMURF1

SUMO1

TAB1

TAB2

TAK1

TLR2

TLR4

TOLLIP

TOM1

TRAF6

UBC13

UEV1A

Ulp1

YopJ

YopP

FURTHER INFORMATION

INSERM

KEGG Pathways on CGAP

The Cancer Genome Anatomy Project (CGAP) Pathway Information

Glossary

PROTEASOME

A large multisubunit protease complex that selectively degrades polyubiquitylated proteins. It is composed of a 20S catalytic complex that is associated with two 19S regulatory particles.

N-END RULE

The ubiquitin-dependent pathway by which target proteins are degraded through their destabilizing N-terminal residues.

TOLL-LIKE RECEPTORS

(TLRs). Type I receptors with leucine-rich extracellular repeats that are involved in pathogen-associated molecular-pattern recognition. Signal transduction by TLRs involves interactions between their cytoplasmic Toll/IL-1 receptor resistance domain (TIR) and TIR-containing adaptors, such as MyD88 and TIRAP.

RHO GTPASES

Proteins that hydrolyse GTP into GDP. These proteins oscillate between a GTP-bound form, which binds and activates effectors, and a GDP-bound inactive form.

MEMBRANE RUFFLES

Plasma-membrane protrusions that form waves and are driven by actin polymerization, which is controlled by Rac.

AB TOXINS

Proteins that are secreted by pathogenic bacteria, such as the diphtheria toxin. These bacterial toxins bind to cells, are endocytosed and inject their catalytic domain into the cytosol, which causes modifications of important components of the host-cellular machinery.

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Boyer, L., Lemichez, E. Targeting of host-cell ubiquitin and ubiquitin-like pathways by bacterial factors. Nat Rev Microbiol 2, 779–788 (2004). https://doi.org/10.1038/nrmicro1005

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