Appearance of crystalloid endoplasmic reticulum in compactin-resistant Chinese hamster cells with a 500-fold increase in 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Chin, Daniel J.; Luskey, Kenneth L.; Anderson, Richard G. W.; Faust, Jerry R.; Goldstein, Joseph L.; Brown, Michael S.

doi:10.1073/pnas.79.4.1185

Cited by 228 publications

(119 citation statements)

References 16 publications

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“…First, it mediates regulation of protein half-life in response to sterol levels (Skalnik et al, 1988;Chun and Simoni, 1992;Hampton and Rine, 1994;Kumagai et al, 1995;Sekler and Simoni, 1995). Second, it is required for stimulation of ER expansion in response to increased HMGCoA reductase levels (Chin et al, 1982;Jingami et al, 1987;Wright et al, 1988;Parrish et al, 1995). For both functions, regions of the membrane domain, including transmembrane segments and the loops that connect them, have been identified as playing particularly critical roles (Gil et al, 1985;Pathak et al, 1986;Jingami et al, 1987;Hampton and Rine, 1994;Kumagai et al, 1995;Parrish et al, 1995;Sekler and Simoni, 1995;Koning et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…The ability to respond to HMG-CoA reductase elevations by generating ER membrane arrays is not unique to yeast but occurs in all cell types that have been examined. For example, in mammalian cells, HMG-CoA reductase induces the formation of hexagonal arrays of smooth ER tubules called crystalloid ER (Chin et al, 1982;Anderson et al, 1983;Orci et al, 1984;Kochevar and Anderson, 1987). In addition, many tissues that produce sterol derivatives, such as steroid hormones, contain characteristic ER membrane arrays (Fawcett, 1981).…”

Section: Introductionmentioning

confidence: 99%

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The Role of the 3-Hydroxy 3-Methylglutaryl Coenzyme A Reductase Cytosolic Domain in Karmellae Biogenesis

Profant¹,

Roberts

Koning

et al. 1999

MBoC

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In all cells examined, specific endoplasmic reticulum (ER) membrane arrays are induced in response to increased levels of the ER membrane protein 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase. In yeast, expression of Hmg1p, one of two yeast HMG-CoA reductase isozymes, induces assembly of nuclear-associated ER stacks called karmellae. Understanding the features of HMG-CoA reductase that signal karmellae biogenesis would provide useful insights into the regulation of membrane biogenesis. The HMG-CoA reductase protein consists of two domains, a multitopic membrane domain and a cytosolic catalytic domain. Previous studies had indicated that the HMG-CoA reductase membrane domain was exclusively responsible for generation of ER membrane proliferations. Surprisingly, we discovered that this conclusion was incorrect: sequences at the carboxyl terminus of HMG-CoA reductase can profoundly affect karmellae biogenesis. Specifically, truncations of Hmg1p that removed or shortened the carboxyl terminus were unable to induce karmellae assembly. This result indicated that the membrane domain of Hmg1p was not sufficient to signal for karmellae assembly. Using β-galactosidase fusions, we demonstrated that the carboxyl terminus was unlikely to simply serve as an oligomerization domain. Our working hypothesis is that a truncated or misfolded cytosolic domain prevents proper signaling for karmellae by interfering with the required tertiary structure of the membrane domain.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Role of the 3-Hydroxy 3-Methylglutaryl Coenzyme A Reductase Cytosolic Domain in Karmellae Biogenesis

Profant¹,

Roberts

Koning

et al. 1999

MBoC

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“…Our results show that such subcompartmentalization of the ER can also be observed in cells not exposed to BFA. On the other hand, morphologically different ER-derived structures have been shown to accumulate high amounts of HMG-CoA reductase in CHO cells (Chin et al, 1982) and to concentrate chondroitin sulfate proteoglycan precursors in chondrocytes (Vertel et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Misfolded major histocompatibility complex class I molecules accumulate in an expanded ER-Golgi intermediate compartment.

Raposo

Santen

Leijendekker

et al. 1995

The Journal of Cell Biology

127

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Abstract. Misfolded membrane proteins are rapidly degraded, often shortly after their synthesis and insertion in the endoplasmic reticulum (ER), but the exact location and mechanisms of breakdown remain unclear. We have exploited the requirement of MHC class I molecules for peptide to achieve their correct conformation: peptide can be withheld by introducing a null mutation for the MHC-encoded peptide transporter, TAP. By withholding TAP-dependent peptides, the vast majority of newly synthesized class I molecules fails to leave the endoplasmic reticulum and is degraded. We used mice transgenic for HLA-B27 on a TAPl-deficient background to allow visualization by immunoelectron microscopy of misfolded HLA-B27 molecules in thymic epithelial cells. In such HLA transgenic animals, the TAP mutation can be considered a genetic switch that allows control over the extent of folding of the protein of interest, HLA-B27, while the rate of synthesis of the constituent subunits remains unaltered.,In TAPl-deficient, HLA-B27 transgenic animals, HLA-B27 molecules fail to assemble correctly, and do not undergo carbohydrate modifications associated with the Golgi apparatus, such as conversion to Endoglycosidase H resistance, and acquisition of sialic acids. We show that such molecules accumulate in an expanded network of tubular and fenestrated membranes. This compartment has its counterpart in normal thymic epithelial cells, and is identified as an ER-Golgi intermediate. We detect the presence of ubiquitin and ubiquitin-conjugating enzymes in association with this compartment, suggesting a nonlysosomal mode of degradation of its contents.

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“…In mammalian cells, HMGR induces the formation of crystalloid ER, which consists of hexagonal arrays of smooth ER tubules that arise from outfoldings of the nuclear envelope (Chin et al, 1982;Pathak et al, 1986). In yeast, Hmglp triggers the formation of karmellae, which are stacked pairs of membranes associated with the nucleus .…”

Section: Introductionmentioning

confidence: 99%

Different subcellular localization of Saccharomyces cerevisiae HMG-CoA reductase isozymes at elevated levels corresponds to distinct endoplasmic reticulum membrane proliferations.

Koning

Roberts

Wright

1996

MBoC

109

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In all eucaryotic cell types analyzed, proliferations of the endoplasmic reticulum (ER) can be induced by increasing the levels of certain integral ER proteins. One of the best characterized of these proteins is HMG-CoA reductase, which catalyzes the rate-limiting step in sterol biosynthesis. We have investigated the subcellular distributions of the two HMG-CoA reductase isozymes in Saccharomyces cerevisiae and the types of ER proliferations that arise in response to elevated levels of each isozyme. At endogenous expression levels, Hmglp and Hmg2p were both primarily localized in the nuclear envelope. However, at increased levels, the isozymes displayed distinct subcellular localization patterns in which each isozyme was predominantly localized in a different region of the ER. Specifically, increased levels of Hmglp were concentrated in the nuclear envelope, whereas increased levels of Hmg2p were concentrated in the peripheral ER. In addition, an Hmg2p chimeric protein containing a 77-amino acid lumenal segment from Hmglp was localized in a pattern that resembled that of Hmglp when expressed at increased levels. Reflecting their different subcellular distributions, elevated levels of Hmglp and Hmg2p induced sets of ER membrane proliferations with distinct morphologies. The ER membrane protein, Sec6lp, was localized in the membranes induced by both Hmglp and Hmg2p green fluorescent protein (GFP) fusions. In contrast, the lumenal ER protein, Kar2p, was present in Hmglp:GFP membranes, but only rarely in Hmg2p:GFP membranes. These results indicated that the membranes synthesized in response to Hmglp and Hmg2p were derived from the ER, but that the membranes were not identical in protein composition. We determined that the different types of ER proliferations were not simply due to quantitative differences in protein amounts or to the different half-lives of the two isozymes. It is possible that the specific distributions of the two yeast HMG-CoA reductase isozymes and their corresponding membrane proliferations may reveal regions of the ER that are specialized for certain branches of the sterol biosynthetic pathway.

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Appearance of crystalloid endoplasmic reticulum in compactin-resistant Chinese hamster cells with a 500-fold increase in 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Cited by 228 publications

References 16 publications

The Role of the 3-Hydroxy 3-Methylglutaryl Coenzyme A Reductase Cytosolic Domain in Karmellae Biogenesis

The Role of the 3-Hydroxy 3-Methylglutaryl Coenzyme A Reductase Cytosolic Domain in Karmellae Biogenesis

Misfolded major histocompatibility complex class I molecules accumulate in an expanded ER-Golgi intermediate compartment.

Different subcellular localization of Saccharomyces cerevisiae HMG-CoA reductase isozymes at elevated levels corresponds to distinct endoplasmic reticulum membrane proliferations.

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