Type 1 polyisoprenoid diphosphate phosphatase modulates geranylgeranyl-mediated control of HMG CoA reductase and UBIAD1

  1. Rania Elsabrouty
  2. Youngah Jo
  3. Seonghwan Hwang
  4. Dong-Jae Jun
  5. Russell A DeBose-Boyd  Is a corresponding author
  1. The University of Texas Southwestern Medical Center, United States

Abstract

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.

Data availability

All data generated or analyzed during this study are included in the manuscript.

Article and author information

Author details

  1. Rania Elsabrouty

    Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Youngah Jo

    Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6779-3891
  3. Seonghwan Hwang

    Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Dong-Jae Jun

    Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Russell A DeBose-Boyd

    Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    russell.debose-boyd@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7452-5227

Funding

National Institutes of Health (HL-20948)

  • Russell A DeBose-Boyd

National Institutes of Health (GM-144039)

  • Russell A DeBose-Boyd

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Suzanne R Pfeffer, Stanford University School of Medicine, United States

Version history

  1. Received: November 7, 2020
  2. Accepted: November 28, 2021
  3. Accepted Manuscript published: November 29, 2021 (version 1)
  4. Version of Record published: December 3, 2021 (version 2)

Copyright

© 2021, Elsabrouty et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Rania Elsabrouty
  2. Youngah Jo
  3. Seonghwan Hwang
  4. Dong-Jae Jun
  5. Russell A DeBose-Boyd
(2021)
Type 1 polyisoprenoid diphosphate phosphatase modulates geranylgeranyl-mediated control of HMG CoA reductase and UBIAD1
eLife 10:e64688.
https://doi.org/10.7554/eLife.64688

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https://doi.org/10.7554/eLife.64688

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