1. Biochemistry and Chemical Biology
  2. Cell Biology

The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase

  1. Marc M Schumacher
  2. Rania Elsabrouty
  3. Joachim Seemann
  4. Youngah Jo
  5. Russell A DeBose-Boyd  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. University of Texas Southwestern Medial Center, United States
  3. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States
https://doi.org/10.7554/eLife.05560
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Cite this article
  1. Marc M Schumacher
  2. Rania Elsabrouty
  3. Joachim Seemann
  4. Youngah Jo
  5. Russell A DeBose-Boyd
(2015)
The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase
eLife 4:e05560.
https://doi.org/10.7554/eLife.05560
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Abstract

Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD-associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K2. Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism. Geranylgeraniol inhibits binding of UBIAD1 to reductase, allowing its degradation and promoting transport of UBIAD1 from the ER to the Golgi. CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation. SCD-associated mutations in UBIAD1 block its displacement from reductase in the presence of geranylgeraniol, thereby preventing degradation of reductase. The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD.

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Author details

  1. Marc M Schumacher

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

  2. Rania Elsabrouty

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

  3. Joachim Seemann

    Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Youngah Jo

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

  5. Russell A DeBose-Boyd

    Department of Molecular Genetics, Howard Hughes Medical Institute, 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.

Copyright

© 2015, Schumacher 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. Marc M Schumacher
  2. Rania Elsabrouty
  3. Joachim Seemann
  4. Youngah Jo
  5. Russell A DeBose-Boyd
(2015)
The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase
eLife 4:e05560.
https://doi.org/10.7554/eLife.05560

Share this article

https://doi.org/10.7554/eLife.05560

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Further reading

    1. Developmental Biology

    Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency

    Youngah Jo, Steven S Kim ... Russell A DeBose-Boyd
    Research Advance Updated

    UbiA prenyltransferase domain-containing protein-1 (UBIAD1) synthesizes the vitamin K subtype menaquinone-4 (MK-4). Previous studies in cultured cells (Schumacher et al., 2015) revealed that UBIAD1 also inhibits endoplasmic reticulum (ER)-associated degradation (ERAD) of ubiquitinated HMG CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway that produces cholesterol and essential nonsterol isoprenoids. Gene knockout studies were previously attempted to explore the function of UBIAD1 in mice; however, homozygous germ-line elimination of the Ubiad1 gene caused embryonic lethality. We now report that homozygous deletion of Ubiad1 is produced in knockin mice expressing ubiquitination/ERAD-resistant HMGCR. Thus, embryonic lethality of Ubiad1 deficiency results from depletion of mevalonate-derived products owing to enhanced ERAD of HMGCR rather than from reduced synthesis of MK-4. These findings provide genetic evidence for the significance of UBIAD1 in regulation of cholesterol synthesis and offer the opportunity in future studies for the discovery of new physiological roles of MK-4.

    1. Biochemistry and Chemical Biology
    2. Cell Biology

    Schnyder corneal dystrophy-associated UBIAD1 inhibits ER-associated degradation of HMG CoA reductase in mice

    Youngah Jo, Jason S Hamilton ... Russell A DeBose-Boyd
    Research Advance Updated

    Autosomal-dominant Schnyder corneal dystrophy (SCD) is characterized by corneal opacification owing to overaccumulation of cholesterol. SCD is caused by mutations in UBIAD1, which utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize vitamin K2. Using cultured cells, we previously showed that sterols trigger binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase (HMGCR), thereby inhibiting its endoplasmic reticulum (ER)-associated degradation (ERAD) (Schumacher et al. 2015). GGpp triggers release of UBIAD1 from HMGCR, allowing maximal ERAD and ER-to-Golgi transport of UBIAD1. SCD-associated UBIAD1 resists GGpp-induced release and is sequestered in ER to inhibit ERAD. We now report knockin mice expressing SCD-associated UBIAD1 accumulate HMGCR in several tissues resulting from ER sequestration of mutant UBIAD1 and inhibition of HMGCR ERAD. Corneas from aged knockin mice exhibit signs of opacification and sterol overaccumulation. These results establish the physiological significance of UBIAD1 in cholesterol homeostasis and indicate inhibition of HMGCR ERAD contributes to SCD pathogenesis.

    1. Biochemistry and Chemical Biology
    2. Microbiology and Infectious Disease

    On the role of VP3-PI3P interaction in birnavirus endosomal membrane targeting

    Flavia A Zanetti, Ignacio Fernandez ... Laura Ruth Delgui
    Research Article

    Birnaviruses are a group of double-stranded RNA (dsRNA) viruses infecting birds, fish, and insects. Early endosomes (EE) constitute the platform for viral replication. Here, we study the mechanism of birnaviral targeting of EE membranes. Using the Infectious Bursal Disease Virus (IBDV) as a model, we validate that the viral protein 3 (VP3) binds to phosphatidylinositol-3-phosphate (PI3P) present in EE membranes. We identify the domain of VP3 involved in PI3P-binding, named P2 and localized in the core of VP3, and establish the critical role of the arginine at position 200 (R200), conserved among all known birnaviruses. Mutating R200 abolishes viral replication. Moreover, we propose a two-stage modular mechanism for VP3 association with EE. Firstly, the carboxy-terminal region of VP3 adsorbs on the membrane, and then the VP3 core reinforces the membrane engagement by specifically binding PI3P through its P2 domain, additionally promoting PI3P accumulation.