title: Small GTPase ARF6 Regulates Endocytic Pathway Leading to Degradation of ATP-Binding Cassette Transporter A1.
abstract: ABCA1 (ATP-binding cassette transporter A1) is the principal protein responsible for cellular cholesterol efflux. Abundance and functionality of ABCA1 is regulated both transcriptionally and post-translationally, with endocytosis of ABCA1 being an important element of post-translational regulation. Functional ABCA1 resides on the plasma membrane but can be internalized and either degraded or recycled back to the plasma membrane. The interaction between the degradative and recycling pathways determines the abundance of ABCA1 and may contribute to the efflux of intracellular cholesterol.
  
  
  
  Here, we show that the principal pathway responsible for the internalization of ABCA1 leading to its degradation in macrophages is ARF6-dependent endocytic pathway. This pathway was predominant in the regulation of ABCA1 abundance and efflux of plasma membrane cholesterol. Conversely, the efflux of intracellular cholesterol was predominantly controlled by ARF6-independent pathways, and inhibition of ARF6 shifted ABCA1 into recycling endosomes enhancing efflux of intracellular cholesterol.
  
  
  
  We conclude that ARF6-dependent pathway is the predominant route responsible for the ABCA1 internalization and degradation, whereas ARF6-independent endocytic pathways may contribute to ABCA1 recycling and efflux of intracellular cholesterol.
authors.affiliation: From the Department of Lipoproteins and Atherosclerosis, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (N.M., A.H., H.L.C., I.C., Y.F., D.S.); Department of Medicine, Karolinska Institute, Stockholm, Sweden (H.L.C.); and Department of Microbiology, Immunology and Tropical Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC (M.B.).
authors.forename: Nigora
authors.initials: N
authors.lastname: Mukhamedova
authors.affiliation: From the Department of Lipoproteins and Atherosclerosis, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (N.M., A.H., H.L.C., I.C., Y.F., D.S.); Department of Medicine, Karolinska Institute, Stockholm, Sweden (H.L.C.); and Department of Microbiology, Immunology and Tropical Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC (M.B.).
authors.forename: Anh
authors.initials: A
authors.lastname: Hoang
authors.affiliation: From the Department of Lipoproteins and Atherosclerosis, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (N.M., A.H., H.L.C., I.C., Y.F., D.S.); Department of Medicine, Karolinska Institute, Stockholm, Sweden (H.L.C.); and Department of Microbiology, Immunology and Tropical Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC (M.B.).
authors.forename: Huanhuan L
authors.initials: HL
authors.lastname: Cui
authors.affiliation: From the Department of Lipoproteins and Atherosclerosis, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (N.M., A.H., H.L.C., I.C., Y.F., D.S.); Department of Medicine, Karolinska Institute, Stockholm, Sweden (H.L.C.); and Department of Microbiology, Immunology and Tropical Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC (M.B.).
authors.forename: Irena
authors.initials: I
authors.lastname: Carmichael
authors.affiliation: From the Department of Lipoproteins and Atherosclerosis, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (N.M., A.H., H.L.C., I.C., Y.F., D.S.); Department of Medicine, Karolinska Institute, Stockholm, Sweden (H.L.C.); and Department of Microbiology, Immunology and Tropical Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC (M.B.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Fu
authors.affiliation: From the Department of Lipoproteins and Atherosclerosis, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (N.M., A.H., H.L.C., I.C., Y.F., D.S.); Department of Medicine, Karolinska Institute, Stockholm, Sweden (H.L.C.); and Department of Microbiology, Immunology and Tropical Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC (M.B.).
authors.forename: Michael
authors.initials: M
authors.lastname: Bukrinsky
authors.affiliation: From the Department of Lipoproteins and Atherosclerosis, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia (N.M., A.H., H.L.C., I.C., Y.F., D.S.); Department of Medicine, Karolinska Institute, Stockholm, Sweden (H.L.C.); and Department of Microbiology, Immunology and Tropical Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC (M.B.). Dmitri.Sviridov@bakeridi.edu.au.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Sviridov
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D034285:Dynamin II / Q000378:metabolism; D004705:Endocytosis; D008264:Macrophages / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D059748:Proteolysis; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D014162:Transfection
chemical_list: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors; D064286:ATP Binding Cassette Transporter 1; D002784:Cholesterol; D034285:Dynamin II; C577833:Abca1 protein, mouse; C000715727:Arf6 protein, mouse; C000608792:DNM2 protein, mouse
keywords: cholesterol; clathrin; endocytosis; endosomes; macrophages