Type 1 polyisoprenoid diphosphate phosphatase modulates geranylgeranyl-mediated control of HMG CoA reductase and UBIAD1
- 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
Russell A DeBose-Boyd
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
- Suzanne R Pfeffer, Stanford University School of Medicine, United States
Publication history
- Received: November 7, 2020
- Accepted: November 28, 2021
- Accepted Manuscript published: November 29, 2021 (version 1)
- 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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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
Further reading
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- Biochemistry and Chemical Biology
- Microbiology and Infectious Disease
Cells steadily adapt their membrane glycerophospholipid (GPL) composition to changing environmental and developmental conditions. While the regulation of membrane homeostasis via GPL synthesis in bacteria has been studied in detail, the mechanisms underlying the controlled degradation of endogenous GPLs remain unknown. Thus far, the function of intracellular phospholipases A (PLAs) in GPL remodeling (Lands cycle) in bacteria is not clearly established. Here, we identified the first cytoplasmic membrane-bound phospholipase A1 (PlaF) from Pseudomonas aeruginosa, which might be involved in the Lands cycle. PlaF is an important virulence factor, as the P. aeruginosa ΔplaF mutant showed strongly attenuated virulence in Galleria mellonella and macrophages. We present a 2.0-Å-resolution crystal structure of PlaF, the first structure that reveals homodimerization of a single-pass transmembrane (TM) full-length protein. PlaF dimerization, mediated solely through the intermolecular interactions of TM and juxtamembrane regions, inhibits its activity. The dimerization site and the catalytic sites are linked by an intricate ligand-mediated interaction network, which might explain the product (fatty acid) feedback inhibition observed with the purified PlaF protein. We used molecular dynamics simulations and configurational free energy computations to suggest a model of PlaF activation through a coupled monomerization and tilting of the monomer in the membrane, which constrains the active site cavity into contact with the GPL substrates. Thus, these data show the importance of the PlaF-mediated GPL remodeling pathway for virulence and could pave the way for the development of novel therapeutics targeting PlaF.
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- Biochemistry and Chemical Biology
- Epidemiology and Global Health
Background:
Few studies have assessed the role of individual plasma cholesterol levels in the association between egg consumption and the risk of cardiovascular diseases. This research aims to simultaneously explore the associations of self-reported egg consumption with plasma metabolic markers and these markers with the risk of cardiovascular disease (CVD).
Methods:
Totally 4778 participants (3401 CVD cases subdivided into subtypes and 1377 controls) aged 30–79 were selected based on the China Kadoorie Biobank. Targeted nuclear magnetic resonance was used to quantify 225 metabolites in baseline plasma samples. Linear regression was conducted to assess associations between self-reported egg consumption and metabolic markers, which were further compared with associations between metabolic markers and CVD risk.
Results:
Egg consumption was associated with 24 out of 225 markers, including positive associations for apolipoprotein A1, acetate, mean HDL diameter, and lipid profiles of very large and large HDL, and inverse associations for total cholesterol and cholesterol esters in small VLDL. Among these 24 markers, 14 were associated with CVD risk. In general, the associations of egg consumption with metabolic markers and of these markers with CVD risk showed opposite patterns.
Conclusions:
In the Chinese population, egg consumption is associated with several metabolic markers, which may partially explain the protective effect of moderate egg consumption on CVD.
Funding:
This work was supported by the National Natural Science Foundation of China (81973125, 81941018, 91846303, 91843302). The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) from the National Key R&D Program of China, National Natural Science Foundation of China (81390540, 81390541, 81390544), and Chinese Ministry of Science and Technology (2011BAI09B01). The funders had no role in the study design, data collection, data analysis and interpretation, writing of the report, or the decision to submit the article for publication.
