TY - JOUR TI - Type 1 polyisoprenoid diphosphate phosphatase modulates geranylgeranyl-mediated control of HMG CoA reductase and UBIAD1 AU - Elsabrouty, Rania AU - Jo, Youngah AU - Hwang, Seonghwan AU - Jun, Dong-Jae AU - DeBose-Boyd, Russell A A2 - Pfeffer, Suzanne R A2 - Walther, Tobias C VL - 10 PY - 2021 DA - 2021/11/29 SP - e64688 C1 - eLife 2021;10:e64688 DO - 10.7554/eLife.64688 UR - https://doi.org/10.7554/eLife.64688 AB - UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4. The prenyltransferase has emerged as a key regulator of sterol-accelerated, endoplasmic reticulum (ER)-associated degradation (ERAD) of HMG CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids including GGpp. Sterols induce binding of UBIAD1 to reductase, inhibiting its ERAD. Geranylgeraniol (GGOH), the alcohol derivative of GGpp, disrupts this binding and thereby stimulates ERAD of reductase and translocation of UBIAD1 to Golgi. We now show that overexpression of Type 1 polyisoprenoid diphosphate phosphatase (PDP1), which dephosphorylates GGpp and other isoprenyl pyrophosphates to corresponding isoprenols, abolishes protein geranylgeranylation as well as GGOH-induced ERAD of reductase and Golgi transport of UBIAD1. Conversely, these reactions are enhanced in the absence of PDP1. Our findings indicate PDP1-mediated hydrolysis of GGpp significantly contributes to a feedback mechanism that maintains optimal intracellular levels of the nonsterol isoprenoid. KW - vesicular transport KW - cholesterol metabolism KW - isoprenoids KW - ER-associated degradation KW - prenylation JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -