Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi.
UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4. Previously, we found that sterols trigger binding of UBIAD1 to endoplasmic reticulum (ER)-localized HMG-CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids, including GGpp. This binding inhibits sterol-accelerated degradation of reductase, which contributes to feedback regulation of the enzyme. The addition to cells of geranylgeraniol (GGOH), which can become converted to GGpp, triggers release of UBIAD1 from reductase, allowing for its maximal degradation and permitting ER-to-Golgi transport of UBIAD1. Here, we further characterize geranylgeranyl-regulated transport of UBIAD1. Results of this characterization support a model in which UBIAD1 continuously cycles between the ER and medial-trans Golgi of isoprenoid-replete cells. Upon sensing a decline of GGpp in ER membranes, UBIAD1 becomes trapped in the organelle where it inhibits reductase degradation. Mutant forms of UBIAD1 associated with Schnyder corneal dystrophy (SCD), a human eye disease characterized by corneal accumulation of cholesterol, are sequestered in the ER and block reductase degradation. Collectively, these findings disclose a novel sensing mechanism that allows for stringent metabolic control of intracellular trafficking of UBIAD1, which directly modulates reductase degradation and becomes disrupted in SCD.
Departments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390-9046.
Marc M
MM
Schumacher
Departments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390-9046.
Dong-Jae
DJ
Jun
Departments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390-9046.
Youngah
Y
Jo
Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046.
Joachim
J
Seemann
Departments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX 75390-9046 Russell.DeBose-Boyd@utsouthwestern.edu.
Russell A
RA
DeBose-Boyd
D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004122:Dimethylallyltranstransferase / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000201:enzymology; D006056:Golgi Apparatus / Q000201:enzymology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics; D011106:Polyisoprenyl Phosphates / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D059748:Proteolysis; D013729:Terpenes / Q000378:metabolism; D014812:Vitamin K / Q000096:biosynthesis / Q000378:metabolism; D024482:Vitamin K 2 / Q000031:analogs & derivatives / Q000378:metabolism
D011106:Polyisoprenyl Phosphates; D013729:Terpenes; D024482:Vitamin K 2; D014812:Vitamin K; C030814:menatetrenone; D006903:Hydroxymethylglutaryl CoA Reductases; D004122:Dimethylallyltranstransferase; C425464:UBIAD1 protein, human; C002963:geranylgeranyl pyrophosphate
UbiA prenyltransferase domain-containing protein-1; endoplasmic reticulum; isoprenoid; lipid metabolism; protein trafficking; vitamin K