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.
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.
Matsuo
Yoshiyuki
Y
Department of Biological Responses, Institute for Virus Research, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
Masutani
Hiroshi
H
Son
Aoi
A
Kizaka-Kondoh
Shinae
S
Yodoi
Junji
J
D000818:Animals; D037281:Calnexin / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism; D002460:Cell Line; D004220:Disulfides / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000201:enzymology; D015796:HLA-B27 Antigen / Q000235:genetics / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007107:Immune System / Q000502:physiology*; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008285:Major Histocompatibility Complex; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010084:Oxidation-Reduction; D017510:Protein Folding; D013312:Stress, Physiological; D013879:Thioredoxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D037282:Calreticulin; D004220:Disulfides; D015796:HLA-B27 Antigen; D015395:Histocompatibility Antigens Class I; D007143:Immunoglobulin Heavy Chains; D008565:Membrane Proteins; C425307:TMX1 protein, human; D037281:Calnexin; D013879:Thioredoxins