Document Detail

Pathogenic bacteria target NEDD8-conjugated cullins to hijack host-cell signaling pathways.
MedLine Citation:
PMID:  20941356     Owner:  NLM     Status:  MEDLINE    
The cycle inhibiting factors (Cif), produced by pathogenic bacteria isolated from vertebrates and invertebrates, belong to a family of molecules called cyclomodulins that interfere with the eukaryotic cell cycle. Cif blocks the cell cycle at both the G₁/S and G₂/M transitions by inducing the stabilization of cyclin-dependent kinase inhibitors p21(waf1) and p27(kip1). Using yeast two-hybrid screens, we identified the ubiquitin-like protein NEDD8 as a target of Cif. Cif co-compartmentalized with NEDD8 in the host cell nucleus and induced accumulation of NEDD8-conjugated cullins. This accumulation occurred early after cell infection and correlated with that of p21 and p27. Co-immunoprecipitation revealed that Cif interacted with cullin-RING ubiquitin ligase complexes (CRLs) through binding with the neddylated forms of cullins 1, 2, 3, 4A and 4B subunits of CRL. Using an in vitro ubiquitylation assay, we demonstrate that Cif directly inhibits the neddylated CUL1-associated ubiquitin ligase activity. Consistent with this inhibition and the interaction of Cif with several neddylated cullins, we further observed that Cif modulates the cellular half-lives of various CRL targets, which might contribute to the pathogenic potential of diverse bacteria.
Grégory Jubelin; Frédéric Taieb; David M Duda; Yun Hsu; Ascel Samba-Louaka; Rika Nobe; Marie Penary; Claude Watrin; Jean-Philippe Nougayrède; Brenda A Schulman; C Erec Stebbins; Eric Oswald
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-09-30
Journal Detail:
Title:  PLoS pathogens     Volume:  6     ISSN:  1553-7374     ISO Abbreviation:  PLoS Pathog.     Publication Date:  2010  
Date Detail:
Created Date:  2010-10-13     Completed Date:  2011-02-14     Revised Date:  2014-09-16    
Medline Journal Info:
Nlm Unique ID:  101238921     Medline TA:  PLoS Pathog     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e1001128     Citation Subset:  IM    
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MeSH Terms
Actins / metabolism
Blotting, Western
Cell Cycle
Cell Nucleus / metabolism
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Cyclin-Dependent Kinase Inhibitor p27
Escherichia coli / pathogenicity*
Escherichia coli Infections / metabolism*,  microbiology,  pathology
Escherichia coli Proteins / metabolism*
Intracellular Signaling Peptides and Proteins / metabolism
Protein Transport
SKP Cullin F-Box Protein Ligases / metabolism*
Signal Transduction*
Two-Hybrid System Techniques
Ubiquitins / genetics,  metabolism*
Grant Support
R01 GM069530/GM/NIGMS NIH HHS; R01GM069530/GM/NIGMS NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Actins; 0/CDKN1A protein, human; 0/CDKN1B protein, human; 0/Cif protein, E coli; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Escherichia coli Proteins; 0/Intracellular Signaling Peptides and Proteins; 0/NEDD8 protein, human; 0/Ubiquitins; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; EC Cullin F-Box Protein Ligases

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