QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 20, Issue 21, 4552-4562, November 1, 2009

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E09-05-0439v1 20/21/4552    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Matsuo, Y. Articles by Yodoi, J. PubMed PubMed Citation Articles by Matsuo, Y. Articles by Yodoi, J.

Physical and Functional Interaction of Transmembrane Thioredoxin-related Protein with Major Histocompatibility Complex Class I Heavy Chain: Redox-based Protein Quality Control and Its Potential Relevance to Immune Responses

Yoshiyuki Matsuo^*, Hiroshi Masutani^*, Aoi Son^*, Shinae Kizaka-Kondoh, and Junji Yodoi^*

*Department of Biological Responses, Institute for Virus Research, and Innovative Techno-Hub for Integrated Medical Bio-imaging, Department of Radiation Oncology and Image-Applied Therapy, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan

Submitted June 1, 2009; Revised August 10, 2009; Accepted August 28, 2009
Monitoring Editor: Ramanujan S. Hegde

In the endoplasmic reticulum (ER), a variety of oxidoreductases classified in the thioredoxin superfamily have been found to catalyze the formation and rearrangement of disulfide bonds. However, the precise function and specificity of the individual thioredoxin family proteins remain to be elucidated. Here, we characterize a transmembrane thioredoxin-related protein (TMX), a membrane-bound oxidoreductase in the ER. TMX exists in a predominantly reduced form and associates with the molecular chaperon calnexin, which can mediate substrate binding. To determine the target molecules for TMX, we apply a substrate-trapping approach based on the reaction mechanism of thiol-disulfide exchange, identifying major histocompatibility complex (MHC) class I heavy chain (HC) as a candidate substrate. Unlike the classical ER oxidoreductases such as protein disulfide isomerase and ERp57, TMX seems not to be essential for normal assembly of MHC class I molecules. However, we show that TMX–class I HC interaction is enhanced during tunicamycin-induced ER stress, and TMX prevents the ER-to-cytosol retrotranslocation of misfolded class I HC targeted for proteasomal degradation. These results suggest a specific role for TMX and its mechanism of action in redox-based ER quality control.

Address correspondence to: Junji Yodoi (yodoi{at}virus.kyoto-u.ac.jp).

Abbreviations used: AMS, 4-acetamido-4'-maleimidylstilbene-2,2'-disulfonic acid; CST, castanospermine; DPS, 4, 4'-dipyridyl disulfide; DTT, dithiothreitol; ER, endoplasmic reticulum; HC, heavy chain; HLA, human leukocyte antigen; MHC, major histocompatibility complex; NEM, N-ethylmaleimide; PDI, protein disulfide isomerase; UPR, unfolded protein response.