Protein Quality Control as a Strategy for Cellular Regulation: Lessons from Ubiquitin-Mediated Regulation of the Sterol Pathway

Hampton, Randolph Y.; Garza, Renee M.

doi:10.1021/cr800544v

Cited by 87 publications

(92 citation statements)

References 91 publications

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“…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] .Second, tagging of firefly luciferase with particular M. truncatula HMGR isoforms (HMGR1 and HMGR3) converted it into a target of MKB1-mediated protein degradation in transfected tobacco (Nicotiana tabacum) protoplasts (Extended Data Fig. 8c).…”

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confidence: 92%

“…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: 92%

“…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%

“…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%

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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: 92%

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confidence: 92%

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%

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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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“…HRD pathway | HRD3 | ERAD | quality control | ubiquitin E ndoplasmic reticulum-associated degradation (ERAD) is a highly conserved quality control pathway responsible for the degradation of both misfolded and normal proteins that limits cellular stress and cytotoxicity caused by an accumulation of misfolded ER proteins (1,2). ERAD occurs through the ubiquitin proteasome pathway, wherein ER-localized ubiquitin ligases covalently modify substrates by attaching multiple copies of the protein ubiquitin, thus tagging them for degradation by cytosolic 26S proteasome (3)(4)(5).…”

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confidence: 99%

Direct and essential function for Hrd3 in ER-associated degradation

Vashistha

Neal

Singh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The HRD (HMG-CoA reductase degradation) pathway is a conserved route of endoplasmic reticulum-associated degradation (ERAD), by which misfolded ER proteins are ubiquitinated and degraded. ERAD substrates are ubiquitinated by the action of the Hrd1 RING-H2 E3 ligase. Hrd1 is always present in a stoichiometric complex with the ER membrane protein Hrd3, which is also required for HRD-dependent degradation. Despite its conserved presence, unequivocal study of Hrd3 function has been precluded by its central role in Hrd1 stability. Loss of Hrd3 causes unrestricted self-degradation of Hrd1, resulting in significant loss of the core ligase. Accordingly, the degree to which Hrd3 functions independently of Hrd1 stabilization has remained unresolved. By capitalizing on our studies of Usa1 in Hrd1 degradation, we have devised a new approach to evaluate Hrd3 functions in ERAD. We now show that Hrd3 has a direct and critical role in ERAD in addition to Hrd1 stabilization. This direct component of Hrd3 is phenotypically as important as Hrd1 in the native HRD complex. Hrd3 was required the E3 activity of Hrd1, rather than substrate or E2 recruitment to Hrd1. Although Hrd1 can function in some circumstances independent of Hrd3, these studies show an indispensable role for Hrd3 in living cells.highly conserved quality control pathway responsible for the degradation of both misfolded and normal proteins that limits cellular stress and cytotoxicity caused by an accumulation of misfolded ER proteins (1, 2). ERAD occurs through the ubiquitin proteasome pathway, wherein ER-localized ubiquitin ligases covalently modify substrates by attaching multiple copies of the protein ubiquitin, thus tagging them for degradation by cytosolic 26S proteasome (3-5).In Saccharomyces cerevisiae, the highly conserved HRD (HMGCoA † reductase degradation) pathway degrades a variety of ERAD substrates, including misfolded luminal proteins (ERAD-L substrates) such as CPY* and integral membrane proteins (ERAD-M substrates) such as Hmg2 (6, 7). Briefly, ERAD-L substrates are ubiquitinated by the HRD complex, which includes the ubiquitin RING-H2 ligase Hrd1, complex members Hrd3, Usa1, and Der1, and luminal factors implicated in substrate selection (3,(8)(9)(10)(11). Conversely, ERAD-M substrates require only Hrd1 and Hrd3 for in vivo degradation (12, 13). Although Hrd1 functions as the core catalytic subunit of the HRD E3 ligase, Hrd3's function has remained enigmatic. Both Hrd1 and Hrd3 are highly conserved, and Hrd1 is rate limiting for degradation of misfolded substrates (3,12,14,15). In yeast, the steady-state levels of Hrd1 strongly depend on Hrd3. At native levels of the HRD components, Hrd3 is required for Hrd1 stability: In a hrd3Δ, Hrd1 half-life drops to less than 15 min, resulting in very low levels (12). This concomitant loss of Hrd1 is due to rapid autodegradation, catalyzed by the RING domain of Hrd1 (16).Because of Hrd3's strong role in maintaining Hrd1 stability, it has remained unclear whether Hrd3 has any other independent ERAD functions. A ...

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Emerging roles of rhomboid‐like pseudoproteases in inflammatory and innate immune responses

Luo

Shu

2017

FEBS Letters

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Edited by Wilhelm JustRhomboid-like pseudoproteases are a conserved superfamily of proteins related to the rhomboid intramembrane serine proteases that lack key catalytic residues. iRhom2, a member of the rhomboid-like pseudoprotease superfamily, regulates the maturation and trafficking of ADAM17 and is associated with inflammatory arthritis. Recent studies demonstrate that iRhom2 is also involved in innate immunity by regulating the trafficking and stability of MITA (also called STING), which is a central adaptor in innate antiviral signalling pathways. Here, we summarize recent progress on the roles and mechanisms of iRhom2 and its homologues in innate immunity and also discuss the links between the physiological functions of iRhoms and immunological diseases.

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Protein Quality Control as a Strategy for Cellular Regulation: Lessons from Ubiquitin-Mediated Regulation of the Sterol Pathway

Cited by 87 publications

References 91 publications

The protein quality control system manages plant defence compound synthesis

The protein quality control system manages plant defence compound synthesis

Direct and essential function for Hrd3 in ER-associated degradation

Emerging roles of rhomboid‐like pseudoproteases in inflammatory and innate immune responses

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