1. Biochemistry and Chemical Biology

Bacterial OTU deubiquitinases regulate substrate ubiquitination upon Legionella infection

  1. Donghyuk Shin
  2. Anshu Bhattacharya
  3. Yi-Lin Cheng
  4. Marta Campos Alonso
  5. Ahmad Reza Mehdipour
  6. Gerbrand J van der Heden van Noort
  7. Huib Ovaa
  8. Gerhard Hummer
  9. Ivan Dikic  Is a corresponding author
  1. Institute of Biochemistry II, Germany
  2. Max Planck Institute of Biophysics, Germany
  3. Leiden University Medical Center, Netherlands
  4. Leiden University Medical Centre, Netherlands
https://doi.org/10.7554/eLife.58277
Share this article
Cite this article
  1. Donghyuk Shin
  2. Anshu Bhattacharya
  3. Yi-Lin Cheng
  4. Marta Campos Alonso
  5. Ahmad Reza Mehdipour
  6. Gerbrand J van der Heden van Noort
  7. Huib Ovaa
  8. Gerhard Hummer
  9. Ivan Dikic
(2020)
Bacterial OTU deubiquitinases regulate substrate ubiquitination upon Legionella infection
eLife 9:e58277.
https://doi.org/10.7554/eLife.58277
  2. Download BibTeX
  3. Download .RIS

Abstract

Legionella pneumophila causes a severe pneumonia known as Legionnaires' disease. During the infection, Legionella injects more than 300 effector proteins into host cells. Among them are enzymes involved in altering the host-ubiquitination system. Here, we identified two Legionella OTU-like deubiquitinases (LOT; LotB (Lpg1621/Ceg23) and LotC (Lpg2529)). The crystal structure of the LotC catalytic core (LotC14-310) was determined at 2.4 Å. Unlike the classical OTU-family, the Legionella OTU-family shows an extended helical lobe between the Cys-loop and the variable loop, which defines them as a unique class of OTU-deubiquitinases. LotB has an additional ubiquitin-binding site (S1'), which enables the specific cleavage of Lys63-linked polyubiquitin chains. By contrast, LotC only contains the S1 site and cleaves different species of ubiquitin chains. MS analysis of LotB and LotC identified different categories of host-interacting proteins and substrates. Together, our results provide new structural insights into bacterial OTU deubiquitinases and indicate distinct roles in host-pathogen interactions.

Data availability

Diffraction data have been deposited in PDB under the accession code 6YK8.

The following data sets were generated

Article and author information

Author details

  1. Donghyuk Shin

    Faculty of Medicine, Institute of Biochemistry II, Frankfurt am Main, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8272-6133

  2. Anshu Bhattacharya

    Faculty of Medicine, Institute of Biochemistry II, Frankfurt am Main, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7383-3594

  3. Yi-Lin Cheng

    Faculty of Medicine, Institute of Biochemistry II, Frankfurt am Main, Germany
    Competing interests
    No competing interests declared.

  4. Marta Campos Alonso

    Faculty of Medicine, Institute of Biochemistry II, Frankfurt am Main, Germany
    Competing interests
    No competing interests declared.

  5. Ahmad Reza Mehdipour

    Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt, Germany
    Competing interests
    No competing interests declared.

  6. Gerbrand J van der Heden van Noort

    Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.

  7. Huib Ovaa

    Cell and Chemical Biology, Leiden University Medical Centre, Leiden, Netherlands
    Competing interests
    No competing interests declared.

  8. Gerhard Hummer

    Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7768-746X

  9. Ivan Dikic

    Faculty of Medicine, Institute of Biochemistry II, Frankfurt am Main, Germany
    For correspondence
    dikic@biochem2.uni-frankfurt.de
    Competing interests
    Ivan Dikic, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8156-9511

Funding

H2020 European Research Council (742720)

  • Donghyuk Shin
  • Anshu Bhattacharya
  • Yi-Lin Cheng
  • Marta Campos Alonso

Deutsche Forschungsgemeinschaft (ID 259139777)

  • Ahmad Reza Mehdipour
  • Gerhard Hummer
  • Ivan Dikic

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2020, Shin et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,995
    views
  • 361
    downloads
  • 30
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Citations by DOI

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Donghyuk Shin
  2. Anshu Bhattacharya
  3. Yi-Lin Cheng
  4. Marta Campos Alonso
  5. Ahmad Reza Mehdipour
  6. Gerbrand J van der Heden van Noort
  7. Huib Ovaa
  8. Gerhard Hummer
  9. Ivan Dikic
(2020)
Bacterial OTU deubiquitinases regulate substrate ubiquitination upon Legionella infection
eLife 9:e58277.
https://doi.org/10.7554/eLife.58277

Share this article

https://doi.org/10.7554/eLife.58277

Categories and tags

Research organism

Further reading

    1. Microbiology and Infectious Disease

    Interplay between bacterial deubiquitinase and ubiquitin E3 ligase regulates ubiquitin dynamics on Legionella phagosomes

    Shuxin Liu, Jiwei Luo ... Zhao-Qing Luo
    Research Article Updated

    Legionella pneumophila extensively modulates the host ubiquitin network to create the Legionella-containing vacuole (LCV) for its replication. Many of its virulence factors function as ubiquitin ligases or deubiquitinases (DUBs). Here, we identify Lem27 as a DUB that displays a preference for diubiquitin formed by K6, K11, or K48. Lem27 is associated with the LCV where it regulates Rab10 ubiquitination in concert with SidC and SdcA, two bacterial E3 ubiquitin ligases. Structural analysis of the complex formed by an active fragment of Lem27 and the substrate-based suicide inhibitor ubiquitin-propargylamide (PA) reveals that it harbors a fold resembling those in the OTU1 DUB subfamily with a Cys-His catalytic dyad and that it recognizes ubiquitin via extensive hydrogen bonding at six contact sites. Our results establish Lem27 as a DUB that functions to regulate protein ubiquitination on L. pneumophila phagosomes by counteracting the activity of bacterial ubiquitin E3 ligases.