Unfolded H2b asialoglycoprotein receptor subunit polypeptides are selectively degraded within the endoplasmic reticulum.
When expressed alone in fibroblasts, approximately 80% of newly made H2b subunits of the human asialoglycoprotein receptor are retained and degraded in the endoplasmic reticulum (ER), whereas about 20% reaches the plasma membrane (1). Thapsigargin, an inhibitor of the ER Ca2+ ATPase, blocks ER folding of the H1 (2) as well as of the H2b subunit, prevents maturation of H2b, and accelerates ER degradation of newly made H2b. The secretory pathway is normal in thapsigargin-treated cells, as monitored by maturation of the vesicular stomatitis virus G protein. The protease inhibitors TLCK and TPCK block the first step in ER degradation of H2, an endoproteolytic cleavage just exoplasmic to the membrane-spanning domain. In protease inhibitor-treated cells, the approximately 80% of H2b that would normally be degraded remains in the ER; as judged by migration on nonreducing SDS-polyacrylamide gel electrophoresis this H2b is improperly folded. Thus, incorrectly folded H2b is normally subjected to ER degradation. In the presence of thapsigargin H2b cannot fold properly and is degraded within the ER. The preferential ER degradation of misfolded or unfolded membrane proteins demonstrated here, functions as a step in ER quality control.
Wikström
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Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142.
Lodish
H F
HF
D016475:3T3 Cells; D000818:Animals; D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D046911:Macromolecular Substances; D051379:Mice; D011489:Protein Denaturation; D017510:Protein Folding; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin; D014107:Tosyllysine Chloromethyl Ketone / Q000494:pharmacology; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D014162:Transfection
D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins; D046911:Macromolecular Substances; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D013729:Terpenes; D014107:Tosyllysine Chloromethyl Ketone; D014108:Tosylphenylalanyl Chloromethyl Ketone; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases