title: STARD4 abundance regulates sterol transport and sensing.
abstract: Nonvesicular transport of cholesterol plays an essential role in the distribution and regulation of cholesterol within cells, but it has been difficult to identify the key intracellular cholesterol transporters. The steroidogenic acute regulatory-related lipid-transfer (START) family of proteins is involved in several pathways of nonvesicular trafficking of sterols. Among them, STARD4 has been shown to increase intracellular cholesteryl ester formation and is controlled at the transcriptional level by sterol levels in cells. We found that STARD4 is very efficient in transporting sterol between membranes in vitro. Cholesterol levels are increased in STARD4-silenced cells, while sterol transport to the endocytic recycling compartment (ERC) and to the endoplasmic reticulum (ER) are enhanced upon STARD4 overexpression. STARD4 silencing attenuates cholesterol-mediated regulation of SREBP-2 activation, while its overexpression amplifies sterol sensing by SCAP/SREBP-2. To analyze STARD4's mode of action, we compared sterol transport mediated by STARD4 with that of a simple sterol carrier, methyl-β-cyclodextrin (MCD), when STARD4 and MCD were overexpressed or injected into cells. Interestingly, STARD4 and cytosolic MCD act similarly by increasing the rate of transfer of sterol to the ERC and to the ER. Our results suggest that cholesterol transport mediated by STARD4 is an important component of the cholesterol homeostasis regulatory machinery.
authors: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors: Bruno
authors: B
authors: Mesmin
authors: Nina H
authors: NH
authors: Pipalia
authors: Frederik W
authors: FW
authors: Lund
authors: Trudy F
authors: TF
authors: Ramlall
authors: Anna
authors: A
authors: Sokolov
authors: David
authors: D
authors: Eliezer
authors: Frederick R
authors: FR
authors: Maxfield
mesh_terms: D020816:Amino Acid Motifs; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000096:biosynthesis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004875:Ergosterol / Q000031:analogs & derivatives / Q000378:metabolism; D004951:Esterification; D036681:Fluorescence Recovery After Photobleaching; D005456:Fluorescent Dyes / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007700:Kinetics; D008081:Liposomes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D059008:Time-Lapse Imaging; D014168:Transferrin / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D002788:Cholesterol Esters; D005456:Fluorescent Dyes; D047908:Intracellular Signaling Peptides and Proteins; D008081:Liposomes; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C497390:SREBF2 protein, human; C102196:SREBP cleavage-activating protein; C456544:STARD4 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D014168:Transferrin; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; C010905:dehydroergosterol; C014409:cholesteryl oleate; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; D004875:Ergosterol