CAND1 exchange factor promotes Keap1 integration into cullin 3-RING ubiquitin ligase during adipogenesis

Dubiel, Dawadschargal; Ordemann, J.; Pratschke, Johann; Dubiel, Wolfgang; Naumann, Michael

doi:10.1016/j.biocel.2015.07.013

Cited by 18 publications

(25 citation statements)

References 35 publications

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“…Overexpression of Flag-CSN7B, but not of Flag-CSN7A, accelerates adipogenic differentiation in LiSa-2 cells During LiSa-2 cell adipogenesis the expression of CSN subunits increases [26]. Permanent downregulation of CSN expression blocks adipogenesis [34].…”

Section: Resultsmentioning

confidence: 99%

“…During LiSa‐2 cell adipogenesis the expression of CSN subunits increases . Permanent downregulation of CSN expression blocks adipogenesis .…”

Section: Resultsmentioning

confidence: 99%

“…2). Increased expression of CSN7B is accompanied with an increase of the CSN complex during adipogenic differentiation [26] indicating a unique role of the CSN CSN7B variant in adipogenesis. Moreover, overexpression of CSN7B, but not that of CSN7A, accelerates adipogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Depletion of CAND1 in Schizosaccaromyces pombe [23], in Saccharomyces cerevisiae [24] or in human cells [22,25] profoundly alters the cellular repertoire of CRL1 complexes. Recently we have shown that CAND1 is an exchange factor for CRL3s as well [26].…”

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confidence: 99%

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Overexpression of COP9 signalosome subunits, CSN7A and CSN7B, exerts different effects on adipogenic differentiation

et al. 2016

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The COP9 signalosome (CSN) is an essential regulator of cullin‐RING‐ubiquitin (Ub) ligases (CRLs), which ubiquitinate important cellular regulators and target them for degradation by the Ub proteasome system (UPS). The CSN exhibits deneddylating activity localized on subunit CSN5, which removes the ubiquitin‐like protein Nedd8 from the cullins of CRLs. CSN‐mediated deneddylation is an important step in the process of CRL remodeling, in which new substrate recognition units are incorporated into Ub ligases to meet changed requirements for proteolysis in cells. For instance, extensive CRL remodeling occurs during adipogenic differentiation when new CRL3s are formed. Diversification of CSN complexes during evolution is most likely another adaptation to meet different cellular requirements. Best known CSN variants are formed by different CSN subunit isoforms. For instance, in plant cells, isoforms have been identified for the MPN‐domain subunits CSN5 (CSN5A and CSN5B) and CSN6 (CSN6A and CSN6B) which form four distinct CSN variants. In mammalian cells CSNCSN7A and CSNCSN7B variants are generated by CSN7 isoforms. We demonstrate that the two variants coexist in human LiSa‐2 cells and in mouse embryonic fibroblasts. During adipogenic differentiation of LiSa‐2 cells CSN7B increases in parallel with an elevation of the total CSN complex. Permanent overexpression of Flag‐CSN7B but not of Flag‐CSN7A accelerates adipogenesis in LiSa‐2 cells indicating a specific function of the CSNCSN7B variant in stimulating adipogenesis. Silencing of CSN7A as well as of CSN7B in LiSa‐2 cells and in mouse embryonic fibroblasts (MEFs) reduces adipogenic differentiation demonstrating that both CSNCSN7A and CSNCSN7B variants are involved in the process.

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Section: Resultsmentioning

confidence: 99%

“…During LiSa‐2 cell adipogenesis the expression of CSN subunits increases . Permanent downregulation of CSN expression blocks adipogenesis .…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Overexpression of COP9 signalosome subunits, CSN7A and CSN7B, exerts different effects on adipogenic differentiation

et al. 2016

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“…Introduction available [9,22]. However, when analyzed in vitro Cand1 has been found to act as an 29 inhibitor of SCF ligase activity [10,11,18,[23][24][25]. In the present study we wish to show 30 that these two findings are not contradictory, but that the exchange activity of Cand1 31 necessarily generates a trade-off between high SCF occupancy and fast SR exchange.…”

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confidence: 83%

Trade-off and flexibility in the dynamic regulation of the cullin-RING ubiquitin ligase repertoire

Straube

Flockerzi

Wolf

2017

Preprint

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Cullin-RING ubiquitin ligases (CRLs) catalyze the ubiquitylation of substrates many of which are degraded by the 26S proteasome. Their modular architecture enables recognition of numerous substrates via exchangeable substrate receptors that competitively bind to a cullin scaffold with high affinity. Due to the plasticity of these interactions there is ongoing uncertainty how cells maintain a flexible CRL repertoire in view of changing substrate loads. Based on a series of in vivo and in vitro studies, different groups proposed that the exchange of substrate receptors is mediated by a protein exchange factor named cullin-associated and neddylation-dissociated 1 (Cand1). Here, we have performed quantitative mathematical modeling to support this hypothesis. To this end we first show that the exchange activity of Cand1 necessarily leads to a trade-off between high ligase activity and fast receptor exchange. Supported by previous in vivo studies we argue that this trade-off yields an optimal Cand1 concentration where the time scale for substrate degradation becomes minimal. In a second step we show through simulations that (i) substrates bias the CRL repertoire leading to preferential assembly of ligases for which substrates are available and (ii) differences in binding affinities create a temporal hierarchy for the degradation of substrates. Together, our results provide general constraints for the operating regimes of molecular exchange systems and suggest that Cand1 endows the CRL network with the properties of an "on demand" system allowing cells to dynamically adjust their CRL repertoire to fluctuating substrate abundances. Author summaryCullin-RING ubiquitin ligases (CRLs) are multisubunit protein complexes where exchangeable substrate receptors (SRs) assemble on a cullin scaffold to mediate ubiquitylation and subsequent degradation of a large variety of substrates. In humans there are hundreds of different CRLs having potentially thousands of substrates. Due to the high affinity of cullin-SR interactions, it has long been a mystery how cells would maintain flexibility to sample the entire SR repertoire in order to match fluctuating substrate loads. Recent experiments indicate that the exchange of different SRs is mediated by a novel protein exchange factor (Cand1). However, the proposed PLOS 1/15peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/168898 doi: bioRxiv preprint first posted online Jul. 26, 2017; biochemical function of Cand1 as a promoter of CRL activity remained difficult to reconcile with previous reports of Cand1 acting as an inhibitor of CRL activity in vitro. Here we show that these two findings are not contradictory, but that the exchange activity of Cand1 necessarily leads to a trade-off between high ligase activity and fast receptor exchange which leads us to predict an optimal Cand1 concentration and a temporal hierarchy for substrate degradation. Our res...

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Cullin‐associated and neddylation‐dissociated 1 regulate reprogramming of lipid metabolism through SKP1‐Cullin‐1‐F‐box^FBXO11‐mediated heterogeneous nuclear ribonucleoprotein A2/B1 ubiquitination and promote hepatocellular carcinoma

Zhang,

Xia,

Yang

et al. 2023

Clinical & Translational Med

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BackgroundEnhanced de novo lipogenesis is essential for hepatocellular carcinoma (HCC). Abnormally high cullin‐associated and neddylation‐dissociated 1 (CAND1) expression is associated with poor clinical prognosis in HCC. The SKP1‐Cullin‐1‐F‐box (SCF) complex consists of the SKP1, Cullin‐1 and F‐box proteins (FBPs) and performs multiple functions including adipogenesis. SCF complex was modulated by CAND1, but Whether and how the CAND1 promotes HCC by regulating SCF complex and lipogenesis are unknown.MethodsHCC samples were used to analyze the correlations between CAND1 expression and clinicopathological characteristics such as survival and prognosis. The in vitro functions of CAND1, FBXO11 and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) were measured by cell proliferation, colony formation and migration assays. The in vivo functions were tested in multiple mouse liver cancer models including patient‐derived xenograft (PDX), cell line‐derived xenograft and AKT/NRASV12‐induced primary liver cancer models. Injections of adeno‐associated virus targeting CAND1 (AAV‐shCAND1) were performed to evaluate the therapeutic efficacy of targeting CAND1. RNA‐Seq and lipidomic assays followed by serial biochemical experiments including mass spectrometry, immunoprecipitation and GST pull‐down were performed to dissect the underlying mechanisms.ResultsCAND1 promoted the expression of lipid synthesis genes by disrupting SCF complex assembly and lipid accumulation. Furthermore, we identified hnRNPA2B1 as a novel F‐box protein 11 (FBXO11)‐binding partner. FBXO11 directly bound to hnRNPA2B1 and promoted hnRNPA2B1 ubiquitination and subsequent degradation. Our evaluations of the therapeutic efficacy of AAV‐shCAND1 injections confirmed that targeting the CAND1‐SCFFBXO11‐hnRNPA2B1A signalling axis was therapeutically effective. CAND1 downregulation significantly reduced the tumour burden in a primary mouse liver cancer model and a PDX model.ConclusionsOur results highlight that CAND1 is associated with poor prognosis in HCC and regulates lipid metabolic reprogramming by dissociating the SCF complex. Targeting the CAND1‐SCFFBXO11‐hnRNPA2B1 axis may be a novel strategy for HCC treatment.

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CAND1 exchange factor promotes Keap1 integration into cullin 3-RING ubiquitin ligase during adipogenesis

Cited by 18 publications

References 35 publications

Overexpression of COP9 signalosome subunits, CSN7A and CSN7B, exerts different effects on adipogenic differentiation

Overexpression of COP9 signalosome subunits, CSN7A and CSN7B, exerts different effects on adipogenic differentiation

Trade-off and flexibility in the dynamic regulation of the cullin-RING ubiquitin ligase repertoire

Cullin‐associated and neddylation‐dissociated 1 regulate reprogramming of lipid metabolism through SKP1‐Cullin‐1‐F‐box^FBXO11‐mediated heterogeneous nuclear ribonucleoprotein A2/B1 ubiquitination and promote hepatocellular carcinoma

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CAND1 exchange factor promotes Keap1 integration into cullin 3-RING ubiquitin ligase during adipogenesis

Cited by 18 publications

References 35 publications

Overexpression of COP9 signalosome subunits, CSN7A and CSN7B, exerts different effects on adipogenic differentiation

Overexpression of COP9 signalosome subunits, CSN7A and CSN7B, exerts different effects on adipogenic differentiation

Trade-off and flexibility in the dynamic regulation of the cullin-RING ubiquitin ligase repertoire

Cullin‐associated and neddylation‐dissociated 1 regulate reprogramming of lipid metabolism through SKP1‐Cullin‐1‐F‐boxFBXO11‐mediated heterogeneous nuclear ribonucleoprotein A2/B1 ubiquitination and promote hepatocellular carcinoma

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Cullin‐associated and neddylation‐dissociated 1 regulate reprogramming of lipid metabolism through SKP1‐Cullin‐1‐F‐box^FBXO11‐mediated heterogeneous nuclear ribonucleoprotein A2/B1 ubiquitination and promote hepatocellular carcinoma