Cellular unfolded protein response against viruses used in gene therapy
- 1Department of Hematology, Christian Medical College, Vellore, India
- 2Centre for Stem Cell Research, Christian Medical College, Vellore, India
Viruses are excellent vehicles for gene therapy due to their natural ability to infect and deliver the cargo to specific tissues with high efficiency. Although such vectors are usually “gutted” and are replication defective, they are subjected to clearance by the host cells by immune recognition and destruction. Unfolded protein response (UPR) is a naturally evolved cyto-protective signaling pathway which is triggered due to endoplasmic reticulum (ER) stress caused by accumulation of unfolded/misfolded proteins in its lumen. The UPR signaling consists of three signaling pathways, namely PKR-like ER kinase, activating transcription factor 6, and inositol-requiring protein-1. Once activated, UPR triggers the production of ER molecular chaperones and stress response proteins to help reduce the protein load within the ER. This occurs by degradation of the misfolded proteins and ensues in the arrest of protein translation machinery. If the burden of protein load in ER is beyond its processing capacity, UPR can activate pro-apoptotic pathways or autophagy leading to cell death. Viruses are naturally evolved in hijacking the host cellular translation machinery to generate a large amount of proteins. This phenomenon disrupts ER homeostasis and leads to ER stress. Alternatively, in the case of gutted vectors used in gene therapy, the excess load of recombinant vectors administered and encountered by the cell can trigger UPR. Thus, in the context of gene therapy, UPR becomes a major roadblock that can potentially trigger inflammatory responses against the vectors and reduce the efficiency of gene transfer.
Keywords: gene therapy, UPR, ER-stress, ER-homeostasis, viral vectors, chaperones
Citation: Sen D, Balakrishnan B and Jayandharan GR (2014) Cellular unfolded protein response against viruses used in gene therapy. Front. Microbiol. 5:250. doi: 10.3389/fmicb.2014.00250
Received: 24 March 2014; Accepted: 07 May 2014;
Published online: 26 May 2014.
Edited by:Shiu-Wan Chan, The University of Manchester, UK
Reviewed by:Kohji Moriishi, University of Yamanashi, Japan
Masahiro Fujimuro, Kyoto Pharmaceutical University, Japan
Copyright © 2014 Sen, Balakrishnan and Jayandharan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Giridhara R. Jayandharan, Department of Hematology, Centre for Stem Cell Research, Christian Medical College, Ida Scudder Road, Vellore-632004, Tamil Nadu, India e-mail: firstname.lastname@example.org