Activation of mammalian unfolded protein response is compatible with the quality control system operating in the endoplasmic reticulum.
Newly synthesized secretory and transmembrane proteins are folded and assembled in the endoplasmic reticulum (ER) where an efficient quality control system operates so that only correctly folded molecules are allowed to move along the secretory pathway. The productive folding process in the ER has been thought to be supported by the unfolded protein response (UPR), which is activated by the accumulation of unfolded proteins in the ER. However, a dilemma has emerged; activation of ATF6, a key regulator of mammalian UPR, requires intracellular transport from the ER to the Golgi apparatus. This suggests that unfolded proteins might be leaked from the ER together with ATF6 in response to ER stress, exhibiting proteotoxicity in the secretory pathway. We show here that ATF6 and correctly folded proteins are transported to the Golgi apparatus via the same route and by the same mechanism under conditions of ER stress, whereas unfolded proteins are retained in the ER. Thus, activation of the UPR is compatible with the quality control in the ER and the ER possesses a remarkable ability to select proteins to be transported in mammalian cells in marked contrast to yeast cells, which actively utilize intracellular traffic to deal with unfolded proteins accumulated in the ER.
Nadanaka
Satomi
S
Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.
Yoshida
Hiderou
H
Kano
Fumi
F
Murata
Masayuki
M
Mori
Kazutoshi
K
D051702:Activating Transcription Factor 6; D000818:Animals; D001324:Autoantigens; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004229:Dithiothreitol / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D037241:Mannose-Binding Lectins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011489:Protein Denaturation; D017510:Protein Folding; D021381:Protein Transport / Q000187:drug effects; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014415:Tunicamycin / Q000494:pharmacology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000378:metabolism
D051702:Activating Transcription Factor 6; D001324:Autoantigens; D004268:DNA-Binding Proteins; C028391:G protein, vesicular stomatitis virus; C097741:Golgin subfamily A member 2; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D014157:Transcription Factors; D014759:Viral Envelope Proteins; D000515:alpha 1-Antitrypsin; D014415:Tunicamycin; C493083:SAR1A protein, human; C513282:SAR1B protein, human; D020559:Monomeric GTP-Binding Proteins; D004229:Dithiothreitol