The ABCA1 Q597R mutant undergoes trafficking from the ER upon ER stress.
Mutations in ATP binding cassette transporter 1 (ABCA1), a membrane protein associated with cellular cholesterol efflux, cause Tangier disease (TD). Previously, we showed that an ABCA1 Q597R mutant (QR) identified in TD is retained in the endoplasmic reticulum. Here, we report that QR trafficking to the plasma membrane was rapidly induced by thapsigargin or DTT, indicating that ER stress-induced QR trafficking. However, pharmacological rescue of ABCA1 activity was not observed. The trafficking was dependent on COPII components and occurred via the ER-Golgi intermediate compartments. Furthermore, we found that QR was more sensitive to ER stress than ATF6, a transcription factor associated with the ER stress response. These results suggest that thapsigargin can be effective in correcting trafficking defects, and raise the possibility that ER stress-induced trafficking is involved in ER quality control.
Tanaka
Arowu R
AR
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Komaba 3-8-1, Meguro-ku, Tokyo 153-8902, Japan.
Kano
Fumi
F
Ueda
Kazumitsu
K
Murata
Masayuki
M
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D051702:Activating Transcription Factor 6 / Q000378:metabolism; D019943:Amino Acid Substitution; D001120:Arginine / Q000737:chemistry / Q000235:genetics; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005973:Glutamine / Q000737:chemistry / Q000235:genetics; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D009154:Mutation; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D013631:Tangier Disease / Q000235:genetics / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology*
C577836:ABCA1 protein, human; C497111:ATF6 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D051702:Activating Transcription Factor 6; D004791:Enzyme Inhibitors; D005973:Glutamine; D019284:Thapsigargin; D001120:Arginine; D002784:Cholesterol