Cytolethal distending toxins require components of the ER-associated degradation pathway for host cell entry.

Authors:
Aria Eshraghi
Aria Eshraghi
University of California
Tempe | United States
Shandee D Dixon
Shandee D Dixon
University of Michigan Medical School
United States
Batcha Tamilselvam
Batcha Tamilselvam
University of Illinois
United States
Emily Jin-Kyung Kim
Emily Jin-Kyung Kim
University of California
Santa Barbara | United States
Amandeep Gargi
Amandeep Gargi
University of California
United States
Julia C Kulik
Julia C Kulik
University of California
Oakland | United States
Robert Damoiseaux
Robert Damoiseaux
University of California
United States
Steven R Blanke
Steven R Blanke
University of Illinois
United States

PLoS Pathog 2014 Jul 31;10(7):e1004295. Epub 2014 Jul 31.

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, California, United States of America.

Intracellular acting protein exotoxins produced by bacteria and plants are important molecular determinants that drive numerous human diseases. A subset of these toxins, the cytolethal distending toxins (CDTs), are encoded by several Gram-negative pathogens and have been proposed to enhance virulence by allowing evasion of the immune system. CDTs are trafficked in a retrograde manner from the cell surface through the Golgi apparatus and into the endoplasmic reticulum (ER) before ultimately reaching the host cell nucleus. However, the mechanism by which CDTs exit the ER is not known. Here we show that three central components of the host ER associated degradation (ERAD) machinery, Derlin-2 (Derl2), the E3 ubiquitin-protein ligase Hrd1, and the AAA ATPase p97, are required for intoxication by some CDTs. Complementation of Derl2-deficient cells with Derl2:Derl1 chimeras identified two previously uncharacterized functional domains in Derl2, the N-terminal 88 amino acids and the second ER-luminal loop, as required for intoxication by the CDT encoded by Haemophilus ducreyi (Hd-CDT). In contrast, two motifs required for Derlin-dependent retrotranslocation of ERAD substrates, a conserved WR motif and an SHP box that mediates interaction with the AAA ATPase p97, were found to be dispensable for Hd-CDT intoxication. Interestingly, this previously undescribed mechanism is shared with the plant toxin ricin. These data reveal a requirement for multiple components of the ERAD pathway for CDT intoxication and provide insight into a Derl2-dependent pathway exploited by retrograde trafficking toxins.

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http://dx.doi.org/10.1371/journal.ppat.1004295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117610PMC

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July 2014
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References

(Supplied by CrossRef)
The cytolethal distending toxin family
CL Pickett et al.
Trends Microbiol 1999

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