Dislocation of type I membrane proteins from the ER to the cytosol is sensitive to changes in redox potential.
The human cytomegalovirus (HCMV) gene products US2 and US11 dislocate major histocompatibility class I heavy chains from the ER and target them for proteasomal degradation in the cytosol. The dislocation reaction is inhibited by agents that affect intracellular redox potential and/or free thiol status, such as diamide and N-ethylmaleimide. Subcellular fractionation experiments indicate that this inhibition occurs at the stage of discharge from the ER into the cytosol. The T cell receptor alpha (TCR alpha) chain is also degraded by a similar set of reactions, yet in a manner independent of virally encoded gene products. Diamide and N-ethylmaleimide likewise inhibit the dislocation of the full-length TCR alpha chain from the ER, as well as a truncated, mutant version of TCR alpha chain that lacks cysteine residues. Cytosolic destruction of glycosylated, ER-resident type I membrane proteins, therefore, requires maintenance of a proper redox potential for the initial step of removal of the substrate from the ER environment.
Tortorella
D
D
Harvard Medical School, Department of Pathology, Boston, Massachusetts 02115, USA.
Story
C M
CM
Huppa
J B
JB
Wiertz
E J
EJ
Jones
T R
TR
Bacik
I
I
Bennink
J R
JR
Yewdell
J W
JW
Ploegh
H L
HL
D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003600:Cytosol / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D003958:Diamide / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D005033:Ethylmaleimide / Q000494:pharmacology; D006031:Glycosylation; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D017510:Protein Folding; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; C074546:US11 protein, herpesvirus; D014764:Viral Proteins; D003958:Diamide; D005033:Ethylmaleimide