Palmitoylation of ATP-binding cassette transporter A1 is essential for its trafficking and function.
ATP-binding cassette transporter (ABC)A1 lipidates apolipoprotein A-I both directly at the plasma membrane and also uses lipids from the late endosomal or lysosomal compartment in the internal lipidation of apolipoprotein A-I. However, how ABCA1 targeting to these specific membranes is regulated remains unknown. Palmitoylation is a dynamically regulated lipid modification that targets many proteins to specific membrane domains. We hypothesized that palmitoylation may also regulate ABCA1 transport and function. Indeed, ABCA1 is robustly palmitoylated at cysteines 3, -23, -1110, and -1111. Abrogation of palmitoylation of ABCA1 by mutation of the cysteines results in a reduction of ABCA1 localization at the plasma membranes and a reduction in the ability of ABCA1 to efflux lipids to apolipoprotein A-I. ABCA1 is palmitoylated by the palmitoyl transferase DHHC8, and increasing DHHC8 protein results in increased ABCA1-mediated lipid efflux. Thus, palmitoylation regulates ABCA1 localization at the plasma membrane, and regulates its lipid efflux ability.
Singaraja
Roshni R
RR
950 West 28th Ave, Vancouver, BC, V5Z 4H4, Canada.
Kang
Martin H
MH
Vaid
Kuljeet
K
Sanders
Shaun S
SS
Vilas
Gonzalo L
GL
Arstikaitis
Pamela
P
Coutinho
Jonathan
J
Drisdel
Renaldo C
RC
El-Husseini
Alaa El Din
Ael D
Green
William N
WN
Berthiaume
Luc
L
Hayden
Michael R
MR
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001692:Biological Transport; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000378:metabolism; D003545:Cysteine; D006801:Humans; D054878:Lipoylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010168:Palmitates / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011993:Recombinant Fusion Proteins; D013329:Structure-Activity Relationship; D014162:Transfection
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D010168:Palmitates; D010743:Phospholipids; D011993:Recombinant Fusion Proteins; D002784:Cholesterol; D000217:Acyltransferases; D003545:Cysteine