title: S-nitrosylation of ARH is required for LDL uptake by the LDL receptor.
abstract: The LDL receptor (LDLR) relies upon endocytic adaptor proteins for internalization of lipoproteins. The results of this study show that the LDLR adaptor autosomal recessive hypercholesterolemia protein (ARH) requires nitric oxide to support LDL uptake. Nitric oxide nitrosylates ARH at C199 and C286, and these posttranslational modifications are necessary for association of ARH with the adaptor protein 2 (AP-2) component of clathrin-coated pits. In the absence of nitrosylation, ARH is unable to target LDL-LDLR complexes to coated pits, resulting in poor LDL uptake. The role of nitric oxide on LDLR function is specific for ARH because inhibition of nitric oxide synthase activity impairs ARH-supported LDL uptake but has no effect on other LDLR-dependent lipoprotein uptake processes, including VLDL remnant uptake and dab2-supported LDL uptake. These findings suggest that cells that depend upon ARH for LDL uptake can control which lipoproteins are internalized by their LDLRs through changes in nitric oxide.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX.
authors.forename: Zhenze
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX.
authors.forename: Shanica
authors.initials: S
authors.lastname: Pompey
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX.
authors.forename: Hongyun
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX.
authors.forename: Jian
authors.initials: J
authors.lastname: Weng
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX.
authors.forename: Rita
authors.initials: R
authors.lastname: Garuti
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX. Electronic address: Peter.Michaely@utsouthwestern.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Michaely
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000235:genetics / Q000378:metabolism; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C573412:LDLR protein, human; C469745:LDLRAP1 protein, human; C500241:Ldlrap1 protein, mouse; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; D009569:Nitric Oxide
keywords: autosomal recessive hypercholesterolemia protein; low density lipoprotein receptor; nitric oxide
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