The emerging family of CULLIN3-RING ubiquitin ligases (CRL3s): cellular functions and disease implications

Genschik, Pascal; Sumara, Izabela; Lechner, Esther

doi:10.1038/emboj.2013.173

Cited by 237 publications

(209 citation statements)

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“…Mutation or dysregulation of cullin-RING E3 ubiquitin ligases (CRLs) can result in the development of cancer and other human diseases [19,24,27,112,113]. Targeting of the ubiquitin-proteasome system for pharmaceutical intervention through proteasome inhibition has been successful in the treatment of multiple myeloma and relapsed mantlecell lymphoma [114,115].…”

Section: Sidebar C | Pharmaceutical Inhibition Of Cullin-ring E3 Ubiqmentioning

confidence: 99%

“…The impact of CRLs on biology is evidenced by the large number of SR proteins identified, including ~200 in mammals (Fig 1) [19,27]. This complexity is undoubtedly reflected in the targets that CRLs ubiquitylate.…”

Section: Introductionmentioning

confidence: 99%

“…The vast majority of these receptors have not been studied in detail, but CRLs have been linked to many biological processes (Sidebar B) [19,27]. This complexity is undoubtedly reflected in the targets that CRLs ubiquitylate.…”

Section: Introductionmentioning

confidence: 99%

“…As described below, many of the regulatory features of CRLs are thought to apply across CRL subfamilies regardless of the identity of the cullin and the specific SR module involved. Thus, for simplicity, we refer here to SR modules as general entities based on conserved features across CRL families.The impact of CRLs on biology is evidenced by the large number of SR proteins identified, including ~200 in mammals (Fig 1) [19,27]. This complexity is undoubtedly reflected in the targets that CRLs ubiquitylate.…”

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confidence: 99%

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Building and remodelling Cullin–RING E3 ubiquitin ligases

2013

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Cullin-RING E3 ubiquitin ligases (CRLs) control a plethora of biological pathways through targeted ubiquitylation of signalling proteins. These modular assemblies use substrate receptor modules to recruit specific targets. Recent efforts have focused on understanding the mechanisms that control the activity state of CRLs through dynamic alterations in CRL architecture. Central to these processes are cycles of cullin neddylation and deneddylation, as well as exchange of substrate receptor modules to re-sculpt the CRL landscape, thereby responding to the cellular requirements to turn over distinct proteins in different contexts. This review is focused on how CRLs are dynamically controlled with an emphasis on how c ullin neddylation cycles are integrated with receptor exchange. Keywords: cullin; ubiquitin; Nedd8; COP9 signalosome; E3 ligase; CAND1 EMBO reports (2013) 14, 1050-1061 published online 15 November 2013; doi:10.1038/embor.2013 See the Glossary for abbreviations used in this article. IntroductionThe proteome is constantly remodelled to suit the needs of the cell, through both synthesis and turnover. Protein turnover is controlled through two main systems: the ubiquitin-proteasome system (UPS) and lysosomal degradation system, including autophagy. Although selective autophagy can provide a means by which to control the abundance of particular organelles and even single proteins, it is best understood as a means to control bulk turnover of cellular components [1]. Conversely, the UPS is a particularly versatile and highly regulated system [2] that allows selective turnover of individual regulatory proteins, even when they are incorporated into higher-order multiprotein assemblies. On the one hand, the entire population of a given protein targeted by the UPS might be subject to rapid tagging with ubiquitin and degradation by the proteasome. On the other hand, the UPS might control the degradation of only a small pool of a particular target protein, for example the population of a protein that has been phosphorylated by an upstream pathway. Thus, the UPS functions in space and time to sculpt the proteome and to control the abundance of active or inactive forms of signalling complexes and cellular machines. As illustrated in this Review, the UPS machinery that controls turnover of a wide swathe of the p roteome is itself dynamically regulated through many mechanisms.The tagging of proteins with particular types of ubiquitin chains serves to mark them for proteasomal degradation. This process occurs through an E1 (ubiquitin-activating enzyme)-E2 (ubiquitinconjugating enzyme)-E3 (ubiquitin ligase) cascade [3][4][5][6][7]. E3 plays a central role in substrate targeting by binding directly to the substrate and presenting target lysine residues to receive ubiquitin from the E2, in the case of RING E3s, or from a ubiquitin-charged cysteine residue in HECT and RBR E3s [6,[8][9][10]. Cullin-RING E3 ubiquitin ligases (CRLs), which were first discovered almost two decades ago [11][12][13], are a superfamily of RING E3...

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Section: Sidebar C | Pharmaceutical Inhibition Of Cullin-ring E3 Ubiqmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Building and remodelling Cullin–RING E3 ubiquitin ligases

2013

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“…Our study unravels a specific requirement of a BTB/POZdomain protein for PEN3 membrane trafficking. The BTB/POZdomain is an evolutionarily conserved motif and protein-protein interaction domain found in proteins involved in a wide range of cellular functions [13][14][15][16][17] . The Arabidopsis genome encodes for around 80 BTB/POZ-domain proteins, of which a small subset act as substrate adaptors for E3 ubiquitin ligase complexes by interacting with CULLIN3 (CUL3) [13][14][15][16] .…”

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confidence: 99%

Arabidopsis BTB/POZ protein-dependent PENETRATION3 trafficking and disease susceptibility

et al. 2017

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The outermost cell layer of plant roots (epidermis) constantly encounters environmental challenges. The epidermal outer plasma membrane domain harbours the PENETRATION3 (PEN3)/ABCG36/PDR8 ATP-binding cassette transporter that confers non-host resistance to several pathogens. Here, we show that the Arabidopsis ENDOPLASMIC RETICULUM-ARRESTED PEN3 (EAP3) BTB/POZ-domain protein specifically mediates PEN3 exit from the endoplasmic reticulum and confers resistance to a root-penetrating fungus, providing prime evidence for BTB/POZ-domain protein-dependent membrane trafficking underlying disease resistance.The PENETRATION3 (PEN3/ABCG36/PDR8) ATP-binding cassette transporter of Arabidopsis thaliana is a crucial component of preinvasive defence against some fungal and bacterial nonhost pathogens entering by direct penetration 1-4 . In above-ground organs, PEN3 is recruited to sites of pathogen attack at the cell surface 3,4 . In seedling roots, PEN3 polarly localizes to the epidermal outer membrane domain in the absence of pathogens 5,6 . Root epidermal cells display four major polar plasma membrane domains: the outer domain facing the environment, the inner domain oriented towards the cortical cell layer, the shootward-oriented, apical, and the root tip-oriented, basal, domain 6 . Proteins in the outer domain that function in regulating the transport of inorganic compounds include, for example, the NIP5;1 boric acid uptake channel 7 . Factors required for PEN3 and NIP5;1 trafficking from the transGolgi network to the outer domain have been identified [8][9][10] , and exocyst complex components promote polar tethering of several outer domain proteins 9,11 . However, factors that specifically mediate trafficking of polar outer membrane cargos involved in responses to root-penetrating pathogens remain to be discovered.In a genetic screen for mislocalization of PEN3 fused to greenfluorescent protein (PEN3-GFP) in the root epidermis of seedlings 9 , we recovered one recessive mutant in which PEN3-GFP localized to a cytoplasmic structure resembling the endoplasmic reticulum (ER) (Fig. 1a-d). This er-arrested pen3-1 (eap3-1) mutation indistinguishably affected localization of PEN3-GFP from that of PEN3-mCherry ( Supplementary Fig. 1a,b), which colocalized with the ER-intrinsic chaperone BIP in the eap3-1 mutant ( Supplementary Fig. 1c,d), corroborating an ER arrest of PEN3.We mapped the eap3-1 mutation to a 275-kb interval on chromosome 3 by recombination mapping (Fig. 1e) combined with mapping and mutation identification by deep sequencing. This interval contained one non-synonymous, single-nucleotide polymorphism that caused a G to A missense mutation resulting in the conversion of glycine 192 to glutamate (eap3 G192E ) in the predicted open reading frame of gene model At3g09030.1 (Fig. 1f). Wild type and homozygous eap3-1 mutants displayed similar EAP3 transcript levels ( Fig. 1g), whereas the SALK_101331 T-DNA insertion located in the single exon of At3g09030 (designated eap3-2) caused a lack of full-length EAP3 messenger ...

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Cellular and Systemic Iron Homeostasis

Crichton

2016

Iron Metabolism

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The emerging family of CULLIN3-RING ubiquitin ligases (CRL3s): cellular functions and disease implications

Cited by 237 publications

References 134 publications

Building and remodelling Cullin–RING E3 ubiquitin ligases

Building and remodelling Cullin–RING E3 ubiquitin ligases

Arabidopsis BTB/POZ protein-dependent PENETRATION3 trafficking and disease susceptibility

Cellular and Systemic Iron Homeostasis

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