Proliferation and Morphogenesis of the Endoplasmic Reticulum Driven by the Membrane Domain of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Plant Cells

Abstract

The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) has a key regulatory role in the mevalonate pathway for isoprenoid biosynthesis and is composed of an endoplasmic reticulum (ER)-anchoring membrane domain with low sequence similarity among eukaryotic kingdoms and a conserved cytosolic catalytic domain. Organized smooth endoplasmic reticulum (OSER) structures are common formations of hypertrophied tightly packed ER membranes devoted to specific biosynthetic and secretory functions, the biogenesis of which remains largely unexplored. We show that the membrane domain of plant HMGR suffices to trigger ER proliferation and OSER biogenesis. The proliferating membranes become highly enriched in HMGR protein, but they do not accumulate sterols, indicating a morphogenetic rather than a metabolic role for HMGR. The N-terminal MDVRRRPP motif present in most plant HMGR isoforms is not required for retention in the ER, which was previously proposed, but functions as an ER morphogenic signal. Plant OSER structures are morphologically similar to those of animal cells, emerge from tripartite ER junctions, and mainly build up beside the nuclear envelope, indicating conserved OSER biogenesis in high eukaryotes. Factors other than the OSER-inducing HMGR construct mediate the tight apposition of the proliferating membranes, implying separate ER proliferation and membrane association steps. Overexpression of the membrane domain of Arabidopsis (Arabidopsis thaliana) HMGR leads to ER hypertrophy in every tested cell type and plant species, whereas the knockout of the HMG1 gene from Arabidopsis, encoding its major HMGR isoform, causes ER aggregation at the nuclear envelope. Our results show that the membrane domain of HMGR contributes to ER morphogenesis in plant cells.

Spatial and temporal regulation of sterol biosynthesis in Nicotiana benthamiana

“…Another possibility for the lower incorporation rate of mevalonate in certain tissues and not others might be with respect to the channeling of mevalonate during sterol biosynthesis. Such metabolic channels or metabolons (Chappell , Newman and Chappell , Winkel , Ferrero et al ) may restrict substrate accessibility such that mevalonate enters the sterol biosynthetic pathway more readily in leaves but not in stems and roots.…”

“…Of significance is the responsiveness of plant HMGR to developmental and environmental signals (Choi et al , Stermer et al , Learned , Korth et al ) and its tight regulation at both the transcriptional and posttranscriptional levels (Stermer et al , Nieto et al , Leivar et al ). Recent findings point to dual functionality (catalytic vs non‐catalytic states) for plant HMGR in isoprenoid production and ER biogenesis (Ferrero et al ).…”

Bicontinuous cubic phases in biological and artificial self-assembled systems

“…Protein-protein and lipid-protein interactions, and/or lipid alterations, appear to play important roles in cubic membrane formation. In plants, it has been reported that the membrane domain of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is key for the proliferation of the ER and the formation of organized smooth endoplasmic reticulum (OSER) [157]. Additionally, it has been reported that the concentration of docosapentaenoic acid (DPA, C22:5n-6) in the cubic membrane of mitochondria in starved amoeba Chaos cells is about 1.6-fold higher than in fed cells.…”

Do inositol supplements enhance phosphatidylinositol supply and thus support endoplasmic reticulum function?

“…Occasionally this membrane expansion has been assessed directly (e.g. by fluorescence microscopy of cells expressing tagged variants of ER-resident proteins or by examination of thin-section electron micrographs (126)(127)(128) ) but more often it is detected less directly as an increase in the expression and/or activity of phospholipid-synthesising enzymesusually CTP:phosphocholine cytidylyltransferase, the rate-limiting enzyme in phosphatidylcholine (PtdCho) synthesis by the Kennedy pathway (23,125,(129)(130)(131) .…”