The ubiquitylation machinery of the endoplasmic reticulum

Hirsch, Christian; Gauss, Robert; Horn, Sabine C.; Neuber, Oliver; Sommer, Thomas

doi:10.1038/nature07962

Cited by 326 publications

(318 citation statements)

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“…A similar inverse correlation between HMGR activity and triterpene levels was observed in transgenic Taraxacum brevicorniculatum plants with silenced rubber synthesis, which was postulated to reflect feedback inhibition from oxidosqualene-derived products or precursors 22 . Multilevel control of HMGR has been well documented in yeast and mammals [10][11][12] , has also been reported in plants 20,23 , and may, for instance, involve phosphorylation. This parallels the situation in yeasts and mammals, where HMGR proteins do not directly interact with HRD-type ERAD Ub-ligases but require INSIG-type proteins as mediators [10][11][12][13] .…”

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confidence: 93%

“…1-2). Several genes corresponding to potential regulatory factors had maximal transcriptional upregulation prior to or concurrent with that of the triterpene saponin genes, including a MYC-like bHLH protein and the JAZ repressor proteins, known elements of the core JA signaling module [4][5][6] , as well as a gene (MT067) corresponding to an RMA-like E3 Ub-ligase 10 , denominated MAKIBISHI1 (MKB1) (Extended Data Fig. 3).…”

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confidence: 99%

“…7a-d). Thus, MKB1 corresponds to an active, ER-localized E3 Ub-ligase, like its mammalian counterparts, which are involved in ERAD 10 .…”

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confidence: 99%

“…Yeast does not possess RMA-type proteins and, as mammals, employs the HRD1-type of ERAD E3 Ub-ligases for sterol control [10][11][12][13] .…”

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confidence: 99%

“…8c). Third, we generated transgenic M. truncatula hairy roots overexpressing truncated HMGR4 proteins (tHMGR4 OE roots), devoid of membrane-spanning domains and localizing to the cytosol, by which they are known to be liberated from ERAD control [10][11][12][13] . tHMGR4 OE roots exhibited a makibishilike phenotype, accumulated monoglycosylated saponins and showed downregulation of saponin gene expression ( The divergent sequences of the plant proteins might have allowed the evolution of a plantspecific gateway to the control of HMGR activity, e.g.…”

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confidence: 99%

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The protein quality control system manages plant defence compound synthesis

Pollier

Moses

González-Guzmán

et al. 2013

Nature

102

126

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Jasmonates (JAs) are ubiquitous oxylipin-derived phytohormones that are essential in the regulation of multiple plant processes, encompassing development, growth and defense. Across the plant kingdom, JAs act as elicitors of the production of bioactive secondary metabolites that serve in the defense against attackers 1-3 . Knowledge on the conserved JA perception and early signaling machineries is increasing 3-6 but the downstream mechanisms that regulate defense metabolism remain largely unknown.Here we show that in the model legume Medicago truncatula JA recruits the endoplasmic reticulum-associated degradation (ERAD) quality control system to manage the production of triterpene saponins, widespread bioactive compounds that share a biogenic origin with sterols 7-9 . An ERAD-type RING membrane-anchor (RMA) E3 ubiquitin (Ub)-ligase is co-expressed with saponin synthesis enzymes to control 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), the rate-limiting enzyme in the supply of the ubiquitous terpene precursor isopentenyl diphosphate. Thereby unrestrained bioactive saponin accumulation is prevented and plant development and integrity secured. This control apparatus is equivalent to the ERAD system that regulates sterol synthesis in yeasts and mammals but that employs distinct E3 Ub-ligases, of the HMGR Degradation 1 (HRD1)-type, to direct destruction of HMGR 10-13 . Hence, the general principles for management of sterol and triterpene saponin biosynthesis are conserved across eukaryotes but can be controlled by divergent regulatory cues. 3To identify regulators of plant triterpene synthesis, we monitored the transcriptome of suspension-cultured M. truncatula cells, known to accumulate saponins following elicitation with JAs 14 . The expression of 8,462 transcripts was visualized by cDNA-AFLP transcript profiling and 282 Methyl JA (MeJA)-responsive tags were identified. The comparable MeJAinduced expression pattern of the genes encoding HMGR, squalene synthase, squalene epoxidase, β-amyrin synthase (BAS) and CYP93E2, enzymes catalyzing steps in triterpene saponin biosynthesis 7-9 , indicated co-regulation ( Fig. 1a and Extended Data Fig. 1-2). Several genes corresponding to potential regulatory factors had maximal transcriptional upregulation prior to or concurrent with that of the triterpene saponin genes, including a MYC-like bHLH protein and the JAZ repressor proteins, known elements of the core JA signaling module 4-6 , as well as a gene (MT067) corresponding to an RMA-like E3 Ub-ligase 10 , denominated MAKIBISHI1 (MKB1) (Extended Data Fig. 3). The early MeJA response of MKB1 was confirmed in the M. truncatula Gene Expression Atlas (MtGEA; http://bioinfo.noble.org/geneatlas/) 15 (Fig. 1b).To assess MKB1 function, we generated transgenic M. truncatula hairy roots in which MKB1 was overexpressed (MKB1 OE roots) or silenced (MKB1 KD roots) (Extended Data Fig. 4a). MKB1 KD roots showed a striking phenotype, in particular when transferred to liquid medium, which caused 'dissociation' of the MKB1 KD roots into 'c...

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confidence: 93%

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confidence: 99%

“…7a-d). Thus, MKB1 corresponds to an active, ER-localized E3 Ub-ligase, like its mammalian counterparts, which are involved in ERAD 10 .…”

mentioning

confidence: 99%

“…Yeast does not possess RMA-type proteins and, as mammals, employs the HRD1-type of ERAD E3 Ub-ligases for sterol control [10][11][12][13] .…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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The protein quality control system manages plant defence compound synthesis

Pollier

Moses

González-Guzmán

et al. 2013

Nature

102

126

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Protein Export from Endoplasmic Reticulum to the Cytosol: In Vitro Methods

Matsumura

Skach

2009

Encyclopedia of Life Sciences

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Newly synthesized proteins that fail to achieve their proper conformation in the endoplasmic reticulum (ER) are recognized by quality control machinery and degraded by the ubiquitin –proteasome pathway. This process is termed ER‐associated degradation (ERAD) and is implicated in a large number of inherited and acquired human diseases characterized by aberrant protein folding. Because ubiquitin , ubiquitination machinery and proteasomes are restricted to the cytosol and nucleus, ERAD substrates must be exported from the ER lumen and/or extracted from the ER membrane before or during degradation. In vitro systems that reconstitute ERAD allow detailed mechanisms of ERAD to be studied independently of ongoing protein synthesis and compensatory feedback mechanisms present in cells. Evidence indicates that retrotranslocation (or dislocation) is tightly regulated via parallel pathways that are adapted to various substrates, molecular lesions and cellular needs and stresses. Key concepts: The endoplasmic reticulum (ER) utilizes a stringent quality control machinery for secretory and transmembrane proteins. Misfolded proteins are recognized by the ER quality control components and degraded by the ubiquitin–proteasome pathway. ER‐associated degradation (ERAD) is a multistep process. Molecular chaperones and lectin‐like proteins play key roles in recognizing misfolded proteins. Ubiquitin ligases modify ERAD substrates by covalent attachment of ubiquitin. Two ATPase associated with various cellular activities, p97 and the 19S proteasome subunit, facilitate retrotranslocation of ERAD substrates and delivery to the 20S proteasome. In vitro systems reconstitute complex ERAD processes. Mechanistic details of ERAD are readily amenable to in vitro manipulation and analysis.

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Protein Quality Control Coming of Age

Meiners

2014

Molecular Aspects of Aging

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The ubiquitylation machinery of the endoplasmic reticulum

Cited by 326 publications

References 99 publications

The protein quality control system manages plant defence compound synthesis

The protein quality control system manages plant defence compound synthesis

Protein Export from Endoplasmic Reticulum to the Cytosol: In Vitro Methods

Protein Quality Control Coming of Age

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