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Title: Discovery of Ubiquitin Deamidases in the Pathogenic Arsenal of Legionella pneumophila

Abstract

Legionella pneumophila translocates the largest known arsenal of over 330 pathogenic factors, called "effectors,'' into host cells during infection, enabling L. pneumophila to establish a replicative niche inside diverse amebas and human macrophages. Here in this paper, we reveal that the L. pneumophila effectors MavC (Lpg2147) and MvcA (Lpg2148) are structural homo-logs of cycle inhibiting factor (Cif) effectors and that the adjacent gene, lpg2149, produces a protein that directly inhibits their activity. In contrast to canonical Cifs, both MavC and MvcA contain an insertion domain and deamidate the residue Gln40 of ubiquitin but not Gln40 of NEDD8. MavC and MvcA are functionally diverse, with only MavC interacting with the human E2-conjugating enzyme UBE2N (Ubc13). MavC deamidates the UBE2N similar to Ub conjugate, disrupting Lys63 ubiquitination and dampening NF-kappa B signaling. Combined, our data reveal a molecular mechanism of host manipulation by pathogenic bacteria and highlight the complex regulatory mechanisms integral to L. pneumophila's pathogenic strategy.

Authors:
 [1];  [1];  [2];  [1];  [1];  [3];  [3];  [4];  [5];  [5];  [6];  [7]
  1. Univ. of Toronto, ON (Canada). Dept. of Chemical Engineering and Applied Chemistry
  2. Univ. of Toronto, ON (Canada). Hospital for Sick Children Research Inst. and Dept. of Biochemistry
  3. Argonne National Lab. (ANL), Argonne, IL (United States). Structural Biology Center, Biosciences Division
  4. Univ. of Toronto, ON (Canada). Dept. of Biochemistry
  5. Univ. of Toronto, ON (Canada). Structural Genomics Consortium; Univ. of Toronto, ON (Canada). Princess Margaret Cancer Centre and Dept. of Medical Biophysics
  6. Univ. of Toronto, ON (Canada). Dept. of Biochemistry; Univ. of Toronto, ON (Canada). Dept. of Molecular Genetics
  7. Univ. of Toronto, ON (Canada). Dept. of Chemical Engineering and Applied Chemistry; Univ. of Calgary, AB (Canada). Dept. of Microbiology, Immunology and Infectious Diseases
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH); Canadian Institutes of Health Research (CIHR); Canada Foundation for Innovation (CFI); Ontario Research Fund; USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1465136
Grant/Contract Number:  
[AC02-06CH11357; GM074942; GM094585; MOP-133406]
Resource Type:
Accepted Manuscript
Journal Name:
Cell Reports
Additional Journal Information:
[ Journal Volume: 23; Journal Issue: 2]; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Valleau, Dylan, Quaile, Andrew T., Cui, Hong, Xu, Xiaohui, Evdokimova, Elena, Chang, Changsoo, Cuff, Marianne E., Urbanus, Malene L., Houliston, Scott, Arrowsmith, Cheryl H., Ensminger, Alexander W., and Savchenko, Alexei. Discovery of Ubiquitin Deamidases in the Pathogenic Arsenal of Legionella pneumophila. United States: N. p., 2018. Web. doi:10.1016/j.celrep.2018.03.060.
Valleau, Dylan, Quaile, Andrew T., Cui, Hong, Xu, Xiaohui, Evdokimova, Elena, Chang, Changsoo, Cuff, Marianne E., Urbanus, Malene L., Houliston, Scott, Arrowsmith, Cheryl H., Ensminger, Alexander W., & Savchenko, Alexei. Discovery of Ubiquitin Deamidases in the Pathogenic Arsenal of Legionella pneumophila. United States. doi:10.1016/j.celrep.2018.03.060.
Valleau, Dylan, Quaile, Andrew T., Cui, Hong, Xu, Xiaohui, Evdokimova, Elena, Chang, Changsoo, Cuff, Marianne E., Urbanus, Malene L., Houliston, Scott, Arrowsmith, Cheryl H., Ensminger, Alexander W., and Savchenko, Alexei. Tue . "Discovery of Ubiquitin Deamidases in the Pathogenic Arsenal of Legionella pneumophila". United States. doi:10.1016/j.celrep.2018.03.060. https://www.osti.gov/servlets/purl/1465136.
@article{osti_1465136,
title = {Discovery of Ubiquitin Deamidases in the Pathogenic Arsenal of Legionella pneumophila},
author = {Valleau, Dylan and Quaile, Andrew T. and Cui, Hong and Xu, Xiaohui and Evdokimova, Elena and Chang, Changsoo and Cuff, Marianne E. and Urbanus, Malene L. and Houliston, Scott and Arrowsmith, Cheryl H. and Ensminger, Alexander W. and Savchenko, Alexei},
abstractNote = {Legionella pneumophila translocates the largest known arsenal of over 330 pathogenic factors, called "effectors,'' into host cells during infection, enabling L. pneumophila to establish a replicative niche inside diverse amebas and human macrophages. Here in this paper, we reveal that the L. pneumophila effectors MavC (Lpg2147) and MvcA (Lpg2148) are structural homo-logs of cycle inhibiting factor (Cif) effectors and that the adjacent gene, lpg2149, produces a protein that directly inhibits their activity. In contrast to canonical Cifs, both MavC and MvcA contain an insertion domain and deamidate the residue Gln40 of ubiquitin but not Gln40 of NEDD8. MavC and MvcA are functionally diverse, with only MavC interacting with the human E2-conjugating enzyme UBE2N (Ubc13). MavC deamidates the UBE2N similar to Ub conjugate, disrupting Lys63 ubiquitination and dampening NF-kappa B signaling. Combined, our data reveal a molecular mechanism of host manipulation by pathogenic bacteria and highlight the complex regulatory mechanisms integral to L. pneumophila's pathogenic strategy.},
doi = {10.1016/j.celrep.2018.03.060},
journal = {Cell Reports},
number = [2],
volume = [23],
place = {United States},
year = {2018},
month = {4}
}

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