Regulating the retention of T-cell receptor alpha chain variants within the endoplasmic reticulum: Ca(2+)-dependent association with BiP.
Immunoglobulin heavy chain binding protein (BiP, GRP 78) coprecipitates with soluble and membrane-associated variants of the T-cell antigen receptor alpha chain (TCR-alpha) which are stably retained within the ER. Chelation of Ca2+ during solubilization of cells leads to the dissociation of BiP from the TCR-alpha variants, which is dependent upon the availability of Mg2+ and hydrolyzable ATP; this suggests that Ca2+ levels can serve to modulate the association/dissociation of these proteins with BiP. In vivo treatment of cells expressing either the soluble or membrane-anchored TCR-alpha variants with the Ca2+ ionophore, A23187, or an inhibitor of an ER Ca(2+)-ATPase, thapsigargin, or the membrane-permeant Ca2+ chelator BAPTA-AM, results in the redistribution of these proteins out of the ER and their subsequent secretion or cell surface expression. Under the same assay conditions, no movement of BiP out of the ER is observed. Taken together, these observations indicate that decreased Ca2+ levels result in the dissociation of a protein bound to BiP, leading to its release from ER retention. These data suggest that the intracellular fate of newly synthesized proteins stably associated with BiP can be regulated by Ca2+ levels in the ER.
Suzuki
C K
CK
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
Bonifacino
J S
JS
Lin
A Y
AY
Davis
M M
MM
Klausner
R D
RD
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005455:Fluorescent Antibody Technique; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D014644:Genetic Variation / Q000235:genetics; D006360:Heat-Shock Proteins; D015151:Immunoblotting; D007137:Immunoglobulin alpha-Chains / Q000235:genetics; D018832:Molecular Chaperones; D010053:Ovary / Q000737:chemistry / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D011233:Precipitin Tests; D011948:Receptors, Antigen, T-Cell / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin
D002273:Carcinogens; D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007137:Immunoglobulin alpha-Chains; D018832:Molecular Chaperones; D011948:Receptors, Antigen, T-Cell; D013729:Terpenes; D000001:Calcimycin; D019284:Thapsigargin; D002118:Calcium