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Unc93b induces apoptotic cell death and is cleaved by host and enteroviral proteases

Harris, KG and Coyne, CB (2015) Unc93b induces apoptotic cell death and is cleaved by host and enteroviral proteases. PLoS ONE, 10 (10).

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Abstract

© 2015 Harris, Coyne.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Unc93b is an endoplasmic reticulum (ER)-resident transmembrane protein that serves to bind and traffic toll-like receptors (TLRs) from the ER to their appropriate subcellular locations for ligand sensing. Because of its role in TLR trafficking, Unc93b is necessary for an effective innate immune response to coxsackievirus B3 (CVB), a positive-sense single stranded RNA virus belonging to the enterovirus family. Here, we show that Unc93b is cleaved by a CVB-encoded cysteine protease (3Cpro) during viral replication. Further, we define a role for Unc93b in the induction of apoptotic cell death and show that expression of wild-type Unc93b, but not a mutant incapable of binding TLRs or exiting the ER (H412R), induces apoptosis. Furthermore, we show that cellular caspases activated during apoptosis directly cleave Unc93b. Interestingly, we show that the 3Cpro- and caspase-mediated cleavage of Unc93b both occur within ten amino acids in the distal N-terminus of Unc93b. Mechanistically, neither caspase-mediated nor 3Cpro-mediated cleavage of Unc93b altered its trafficking function, inhibited its role in facilitating TLR3 or TLR8 signaling, or altered its apoptosis- inducing effects. Taken together, our studies show that Unc93b is targeted by both viral- and host cell-specific proteases and identify a function of Unc93b in the induction of apoptotic cell death.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Harris, KG
Coyne, CB
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorHsieh, Yi-HsienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 28 October 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 10
DOI or Unique Handle: 10.1371/journal.pone.0141383
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Molecular Genetics
Refereed: Yes
Date Deposited: 23 Aug 2016 14:43
Last Modified: 13 Oct 2017 20:56
URI: http://d-scholarship.pitt.edu/id/eprint/28371

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