Inositol hexakisphosphate (IP6) generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function
Paul SchererYan DingZhiqing LiuJing XuHaibin MaoJames C. BarrowNing WeiNing ZhengSolomon H. SnyderFeng Rao
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Abstract:
Significance The regulation of ubiquitylation is critical to maintain proteomic and cellular homeostasis. The cullin-RING E3 ubiquitin ligases (CRLs) mediate one-fifth of all ubiquitylation, but their regulation is largely unknown. Here, we describe how the generation of a small metabolite, inositol hexakisphosphate (IP6), locally switches two CRLs from their active to their inactive state by means of stabilizing their interaction with an inhibitor: the constitutive photomorphogenesis 9 signalosome. Furthermore, we demonstrate the physiologic consequences of IP6 depletion on CRL dysregulation, CRL substrate levels, and global cellular phenotypes. Targeting IP6 synthesis synergizes with the cytotoxic effect of CRL inhibition, which may have therapeutic relevance.Keywords:
COP9 signalosome
Cullin
NEDD8
Neddylation
Skp1
Cullin
COP9 signalosome
Ubiquitin-Protein Ligases
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COP9 signalosome
Degradation
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NEDD8
Cullin
COP9 signalosome
Neddylation
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Cullin 戒指 E3 ligases (CRL ) 调整植物 developmentand 的不同方面被他们的 cullin 子单元的修正与象 ubiquitin 一样蛋白质 NEDD8 激活(表示的神经先锋房间发展地下面调整 8 )(neddylation ) 并且由 NEDD8 移动(deneddylation ) 撤销了。CONSTITUTIVELY PHOTOMORPHOGENIC9 (COP9 ) signalosome (CSN ) 行为作为由回复的 CRLsactivity 的一个分子的开关，他们的 neddylation 地位，而是它对胚胎、早的幼苗开发的贡献仍然保持糟糕描绘了。这里，我们分析了 csn 异种的 phenotypic 缺点并且在胚胎、早的幼苗开发期间监视了 cullin deneddylation/neddylation 比率。Weshow 当 csn 异种能完成 embryogenesis 时(以更慢的步的虽然比野类型) 并且能发芽(以减少的率的虽然) ，他们日益增多地在 germinationuntil 之上失去分裂组织活动他们变得不能支撑生长。我们也证明 cullin 蛋白质的多数是日益增多地 neddylated 在在种子萌芽之上的种子成熟和 becomedeneddylated 的迟了的阶段期间。在 cullin neddylation 地位的这发展地调整的移动在 csn 异种是不在的。我们断定 CSN 和它的 cullin deneddylation 活动被要求在 Arabidopsis 支撑 postembryonic 分裂组织功能。
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COP9 signalosome
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NEDD8 conjugation of Cullin has an important role in ubiquitin-mediated protein degradation. The COP9 signalosome, of which CSN5 is the major catalytic subunit, is a major Cullin deneddylase. Another deneddylase, Deneddylase 1, has also been shown to process the Nedd8 precursor. In Drosophila, the DEN1 mutants do not have increased levels of Cullin neddylation, but instead show a significant decrease in neddylated Cullin. This characteristic decrease in neddylated Cullins in the DEN1null background can be rescued by UAS-dDEN1WT overexpression but not by overexpression of mature NEDD8, indicating that this phenotype is distinct from the NEDD8-processing function of DEN1. We examined the role of DEN1-CSN interaction in regulating Cullin neddylation. Overexpression of DEN1 in a CSN5hypo background slightly reduced unneddylated Cullin levels. The CSN5, DEN1 double mutation partially rescues the premature lethality associated with the CSN5 single mutation. These results suggest that DEN1 regulates Cullin neddylation by suppressing CSN deneddylase activity.
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The COP9 signalosome inhibits the activity of Cullin-RING E3 ubiquitin ligases by removing Nedd8 modifications from their Cullin subunits. Neddylation renders these complexes catalytically active, but deneddylation is also necessary for them to exchange adaptor subunits and avoid auto-ubiquitination. Although deneddylation is thought to be the primary function of the COP9 signalosome, additional activities have been ascribed to some of its subunits. We recently showed that COP9 subunits protect the transcriptional repressor and tumor suppressor Capicua from two distinct modes of degradation. Deneddylation by the COP9 signalosome inactivates a Cullin 1 complex that ubiquitinates Capicua following its phosphorylation by MAP kinase in response to Epidermal Growth Factor Receptor signaling. The CSN1b subunit also stabilizes unphosphorylated Capicua to control its basal level, independently of the deneddylase function of the complex. Here we further examine the importance of deneddylation for COP9 functions in vivo. We use an uncleavable form of Nedd8 to show that preventing deneddylation does not reproduce the effects of loss of COP9. In contrast, in the presence of COP9, conjugation to uncleavable Nedd8 renders Cullins unable to promote the degradation of their substrates. Our results suggest that irreversible neddylation prolongs COP9 binding to and inhibition of Cullin-based ubiquitin ligases.
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Neddylation
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Neddylation
NEDD8
Cullin
COP9 signalosome
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Neddylation
NEDD8
COP9 signalosome
Cullin
Skp1
Protein Degradation
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The COP9 signalosome (CSN) is composed of eight distinct subunits and is highly homologous to the lid sub-complex of the 26S proteasome. CSN was initially defined as a repressor of photomorphogenesis in Arabidopsis, and it has now been found to participate in diverse cellular and developmental processes in various eukaryotic organisms. Recently, CSN was revealed to have a metalloprotease activity centered in the CSN5/Jab1 subunit, which removes the post-translational modification of a ubiquitin-like protein, Nedd8/Rub1, from the cullin component of SCF ubiquitin E3 ligase (i.e., de-neddylation). In addition, CSN is associated with de-ubiquitination activity and protein kinase activities capable of phosphorylating important signaling regulators. The involvement of CSN in a number of cellular and developmental processes has been attributed to its control over ubiquitin-proteasome-mediated protein degradation.
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NEDD8
Cullin
Neddylation
Immunoprecipitation
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