Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Cell Biol. 169 (4): 603-612

Copyright © 2005 by the Rockefeller University Press.


Endoplasmic reticulum stress modulates the response of myelinating oligodendrocytes to the immune cytokine interferon-{gamma}

Wensheng Lin1, Heather P. Harding2, David Ron2, , and Brian Popko1

1 Jack Miller Center for Peripheral Neuropathy, Department of Neurology, University of Chicago, Chicago, IL 60637
2 The Skirball Institute, New York University School of Medicine, New York, NY 10016

Correspondence to Brian Popko: bpopko{at}

Abstract: I*nterferon-{gamma} (IFN-{gamma}) is believed to contribute to immune-mediated demyelinating disorders by targeting the myelin-producing oligodendrocyte, a cell known to be highly sensitive to the disruption of protein synthesis and to the perturbation of the secretory pathway. We found that apoptosis induced by IFN-{gamma} in cultured rat oligodendrocytes was associated with endoplasmic reticulum (ER) stress. ER stress also accompanied oligodendrocyte apoptosis and hypomyelination in transgenic mice that inappropriately expressed IFN-{gamma} in the central nervous system (CNS). Compared with a wild-type genetic background, the enforced expression of IFN-{gamma} in mice that were heterozygous for a loss of function mutation in pancreatic ER kinase (PERK) dramatically reduced animal survival, promoted CNS hypomyelination, and enhanced oligodendrocyte loss. PERK encodes an ER stress–inducible kinase that phosphorylates eukaryotic translation initiation factor 2{alpha} and specifically maintains client protein homeostasis in the stressed ER. Therefore, the hypersensitivity of PERK+/– mice to IFN-{gamma} implicates ER stress in demyelinating disorders that are induced by CNS inflammation.

Abbreviations used in this paper: ATF, activating transcription factor; BIP, binding immunoglobulin protein; CGT, ceramide galactosyltransferase; CHOP, CAATT enhancer–binding protein homologous protein; CNP, 2'3'-cyclic nucleotide 3'-phosphodiesterase; CNS, central nervous system; GFAP, glial fibrillary acidic protein; E 14, embryonic day 14; eIF, eukaryotic translation initiation factor; IFN-{gamma}, interferon-{gamma}; iNOS, inducible NO synthase; IRE, inositol requiring; MBP, myelin basic protein; MHC, major histocompatibility complex; MS, multiple sclerosis; NO, nitric oxide; PERK, pancreatic ER kinase; PLP, proteolipid protein; PMD, Pelizaeus-Merzbacher disease; tTA, tetracycline-controlled transactivator; VWM, leukoencephalopathy with vanishing white matter.

Oligodendrocyte-Specific Activation of PERK Signaling Protects Mice against Experimental Autoimmune Encephalomyelitis.
W. Lin, Y. Lin, J. Li, A. G. Fenstermaker, S. W. Way, B. Clayton, S. Jamison, H. P. Harding, D. Ron, and B. Popko (2013)
J. Neurosci. 33, 5980-5991
   Abstract »    Full Text »    PDF »
Mutation of sec63 in zebrafish causes defects in myelinated axons and liver pathology.
K. R. Monk, M. G. Voas, C. Franzini-Armstrong, I. S. Hakkinen, and W. S. Talbot (2013)
Dis. Model. Mech. 6, 135-145
   Abstract »    Full Text »    PDF »
Neuroinflammation and Endoplasmic Reticulum Stress Are Coregulated by Crocin To Prevent Demyelination and Neurodegeneration.
A. M. Deslauriers, A. Afkhami-Goli, A. M. Paul, R. K. Bhat, S. Acharjee, K. K. Ellestad, F. Noorbakhsh, M. Michalak, and C. Power (2011)
J. Immunol. 187, 4788-4799
   Abstract »    Full Text »    PDF »
Endoplasmic Reticulum Stress-activated C/EBP Homologous Protein Enhances Nuclear Factor-{kappa}B Signals via Repression of Peroxisome Proliferator-activated Receptor {gamma}.
S.-H. Park, H. J. Choi, H. Yang, K. H. Do, J. Kim, D. W. Lee, and Y. Moon (2010)
J. Biol. Chem. 285, 35330-35339
   Abstract »    Full Text »    PDF »
In vivo cellular adaptation to ER stress: survival strategies with double-edged consequences.
K. Y. Tsang, D. Chan, J. F. Bateman, and K. S. E. Cheah (2010)
J. Cell Sci. 123, 2145-2154
   Abstract »    Full Text »    PDF »
ER stress and the unfolded protein response in intestinal inflammation.
M. A. McGuckin, R. D. Eri, I. Das, R. Lourie, and T. H. Florin (2010)
Am J Physiol Gastrointest Liver Physiol 298, G820-G832
   Abstract »    Full Text »    PDF »
ZFP191 is required by oligodendrocytes for CNS myelination.
S. Y. B. Howng, R. L. Avila, B. Emery, M. Traka, W. Lin, T. Watkins, S. Cook, R. Bronson, M. Davisson, B. A. Barres, et al. (2010)
Genes & Dev. 24, 301-311
   Abstract »    Full Text »    PDF »
The Degree of Folding Instability of the Envelope Protein of a Neurovirulent Murine Retrovirus Correlates with the Severity of the Neurological Disease.
J. L. Portis, P. Askovich, J. Austin, Y. Gutierrez-Cotto, and F. J. McAtee (2009)
J. Virol. 83, 6079-6086
   Abstract »    Full Text »    PDF »
Vaticanol B, a resveratrol tetramer, regulates endoplasmic reticulum stress and inflammation.
Y. Tabata, K. Takano, T. Ito, M. Iinuma, T. Yoshimoto, H. Miura, Y. Kitao, S. Ogawa, and O. Hori (2007)
Am J Physiol Cell Physiol 293, C411-C418
   Abstract »    Full Text »    PDF »
Interferon-{gamma}-Oligodendrocyte Interactions in the Regulation of Experimental Autoimmune Encephalomyelitis.
R. Balabanov, K. Strand, R. Goswami, E. McMahon, W. Begolka, S. D. Miller, and B. Popko (2007)
J. Neurosci. 27, 2013-2024
   Abstract »    Full Text »    PDF »
Suppressor of cytokine signaling 1 expression protects oligodendrocytes from the deleterious effects of interferon-gamma..
R. Balabanov, K. Strand, A. Kemper, J. Y. Lee, and B. Popko (2006)
J. Neurosci. 26, 5143-5152
   Abstract »    Full Text »    PDF »
Interferon-{gamma} inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress.
W. Lin, A. Kemper, J. L. Dupree, H. P. Harding, D. Ron, and B. Popko (2006)
Brain 129, 1306-1318
   Abstract »    Full Text »    PDF »
Different intracellular pathomechanisms produce diverse Myelin Protein Zero neuropathies in transgenic mice..
L. Wrabetz, M. D'Antonio, M. Pennuto, G. Dati, E. Tinelli, P. Fratta, S. Previtali, D. Imperiale, J. Zielasek, K. Toyka, et al. (2006)
J. Neurosci. 26, 2358-2368
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882