The human Dcn1-like protein DCNL3 promotes Cul3 neddylation at membranes

Meyer-Schaller, Nathalie; Chou, Yang-Chieh; Sumara, Izabela; Martin, Dale D.O.; Kurz, Thimo; Katheder, Nadja Sandra; Hofmann, Kay; Berthiaume, Luc G.; Sicheri, Frank; Peter, Matthias

doi:10.1073/pnas.0812528106

Cited by 76 publications

(100 citation statements)

References 27 publications

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“…To provide further evidence, we studied the localization of CUL3 in HeLa cells. In these cells, CUL3 must be recruited from the nucleus to the cytoplasm, where it is neddylated and activated (13). Here, we confirmed that CUL3 was predominantly nuclear in unstimulated HeLa cells and recruited to the cytoplasm when KLHL3 was cotransfected.…”

Section: And Colleaguessupporting

confidence: 72%

Hyperkalemic hypertension–associated cullin 3 promotes WNK signaling by degrading KLHL3

et al. 2014

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Section: And Colleaguessupporting

confidence: 72%

Hyperkalemic hypertension–associated cullin 3 promotes WNK signaling by degrading KLHL3

et al. 2014

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“…Nevertheless, the role of the five DCN orthologues in mammals remains largely unknown. The PONY domains of the individual family members can activate several cullin-RBX pairs to varying degrees, but the impact on in vivo neddylation has been difficult to assess with RNA interference, probably because of at least partial redundancy among the various DCN family members [63,64]. …”

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confidence: 99%

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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“…Similarly, it has been shown that DCNL3 knockdown stabilizes the CUL3 substrate NRF2 (37). DCNL1, DCNL2 (long isoform), and DCNL3 have been shown to be promiscuous in their ability to bind multiple cullins (37). Although there is promiscuity among DCNL members in binding to CUL2, DCNL1 was most associated with neddylated CUL2, followed by DCNL3 (see Fig.…”

Section: Resultsmentioning

confidence: 98%

“…DCNL1 promotes neddylation of CUL2 (Fig. 2) as well as other cullins (12), and the engagement of HIF1␣ to ECV has been shown previously to promote CUL2 neddylation (27,37). We asked whether substrate-mediated CUL2 neddylation is coordinated with DCNL1.…”

Section: Resultsmentioning

confidence: 99%

“…We show here that VHL, SOCS1, and SOCS2, but not SOCS3, interact with DCNL1, suggesting that all substrate-conferring proteins do not bind to DCNL1. In this regard, there are additional DCNL proteins in humans (DCNL2-1, DCNL2-2, DCNL3, DCNL4-1, DCNL4-2, and DCNL5), and DCNL1 and DCNL2-1 have been shown to bind CUL1, CUL2, CUL3, CUL4A, CUL4B, and CUL5, while DCNL3 has been shown to stimulate CUL3 neddylation at the plasma membrane to possibly facilitate ubiquitylation of membrane-associated substrates (37). This would suggest that certain CRL3 substrates upon bind-ing to their cognate substrate receptors would increase recruitment of DCNL3, but not necessarily of DCNL1, for subsequent neddylation of CUL3.…”

Section: Discussionmentioning

confidence: 99%

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DCNL1 Functions as a Substrate Sensor and Activator of Cullin 2-RING Ligase

Heir

Sufan

Greer

et al. 2013

Molecular and Cellular Biology

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Substrate engagement by F-box proteins promotes NEDD8 modification of cullins, which is necessary for the activation of cullin-RING E3 ubiquitin ligases (CRLs). However, the mechanism by which substrate recruitment triggers cullin neddylation remains unclear. Here, we identify DCNL1 (defective in cullin neddylation 1-like 1) as a component of CRL2 called ECV (elongins BC/CUL2/VHL) and show that molecular suppression of DCNL1 attenuates CUL2 neddylation. DCNL1 via its DAD patch binds to CUL2 but is also able to bind VHL independent of CUL2 and the DAD patch. The engagement of the substrate hypoxia-inducible factor 1␣ (HIF1␣) to the substrate receptor VHL increases DCNL1 binding to VHL as well as to CUL2. Notably, an engineered mutant form of HIF1␣ that associates with CUL2, but not DCNL1, fails to trigger CUL2 neddylation and retains ECV in an inactive state. These findings support a model in which substrate engagement prompts DCNL1 recruitment that facilitates the initiation of CUL2 neddylation and define DCNL1 as a "substrate sensor switch" for ECV activation. Cullin-RING ligases (CRLs), the largest family of E3 ubiquitin ligases, are multiprotein complexes involved in protein degradation (1, 2). They are assembled on a cullin scaffold (CUL1, CUL2, CUL3, CUL4A, CUL4B, and CUL5) and contain a RING finger protein (RBX1 or RBX2) at the cullin C-terminal domain (CTD) as well as a substrate receptor, which generally associates with the cullin N-terminal domain (NTD) via adaptor proteins (2). CUL3-based CRLs are the exception in which the Broad complex, Tramtrack, and Bric-a-Brac (BTB)-domain containing protein mediates both substrate specificity and binding to CUL3 without the need of adaptor proteins (3).The process of attaching ubiquitin onto a CRL substrate requires three enzymes. Using ATP, an E1 activating enzyme forms a thioester bond between its catalytic cysteine residue and the C-terminal carboxyl group of ubiquitin (4). The activated ubiquitin is then transferred onto the catalytic cysteine of an E2 conjugating enzyme (4). CRL through RBX1/2 helps transfer ubiquitin from E2 onto a lysine residue on the bound substrate (2). Neddylation, the process of conjugating the ubiquitin-like protein NEDD8 onto a substrate, follows an analogous cascade (5, 6). Cullins are modified by NEDD8 (7). Structural studies involving the CTD of CUL5 (CUL5 CTD )-RBX1 and NEDD8ϳCUL5 CTD -RBX1 have demonstrated that in an unneddylated state, RBX1 has limited movement due to inhibitory cullin subdomains, thus restraining its ability to recruit ubiquitin-charged E2 (8). Neddylation causes a conformational change in cullin structure that releases RBX1 from a confined configuration to enhance the binding of ubiquitin-charged E2 and thus CRL ubiquitylation capability (8, 9).The molecular events involved in the process of neddylation of cullins are not as straightforward as the resulting effects. For CUL1 neddylation to take place, rotation of the RING domain of RBX1 is needed in order to bring the catalytic Cys111 of UBC12 (NEDD8 E2 enz...

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The human Dcn1-like protein DCNL3 promotes Cul3 neddylation at membranes

Abstract: Cullin ͉ DCUN1D ͉ Nedd8 ͉ ubiquitin ͉ squamous cell carcinoma-related oncogene

Cited by 76 publications

References 27 publications

Hyperkalemic hypertension–associated cullin 3 promotes WNK signaling by degrading KLHL3

Hyperkalemic hypertension–associated cullin 3 promotes WNK signaling by degrading KLHL3

Building and remodelling Cullin–RING E3 ubiquitin ligases

DCNL1 Functions as a Substrate Sensor and Activator of Cullin 2-RING Ligase

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