Moonlighting and pleiotropy within two regulators of the degradation machinery: the proteasome lid and the CSN

Pick, Elah; Bramasole, Laylan

doi:10.1042/bst20140227

Cited by 9 publications

(9 citation statements)

References 60 publications

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“…Consistent with this idea, the top two SNPs identified in our screen are in putative regulatory regions of the COPS7B gene (as well as 24 other alleles in the same hapblock with p<10 −6 ). This protein is part of the COP9 signalosome, which has been implicated both in regulating ubiquitin-mediated proteolysis ( Pick and Bramasole, 2014 ), and in regulating circadian behavior of Neurospora crassa and Drosophila melanogaster ( He et al, 2005 ; Knowles et al, 2009 ). Therefore, understanding how COPS7B affects circadian function could provide important clues to the mechanisms of genetic influence upon human circadian clocks.…”

Section: Resultsmentioning

confidence: 99%

The genomic landscape of human cellular circadian variation points to a novel role for the signalosome

Gaspar

Howald

Popadin

et al. 2017

eLife

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The importance of natural gene expression variation for human behavior is undisputed, but its impact on circadian physiology remains mostly unexplored. Using umbilical cord fibroblasts, we have determined by genome-wide association how common genetic variation impacts upon cellular circadian function. Gene set enrichment points to differences in protein catabolism as one major source of clock variation in humans. The two most significant alleles regulated expression of COPS7B, a subunit of the COP9 signalosome. We further show that the signalosome complex is imported into the nucleus in timed fashion to stabilize the essential circadian protein BMAL1, a novel mechanism to oppose its proteasome-mediated degradation. Thus, circadian clock properties depend in part upon a genetically-encoded competition between stabilizing and destabilizing forces, and genetic alterations in these mechanisms provide one explanation for human chronotype.

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Section: Resultsmentioning

confidence: 99%

The genomic landscape of human cellular circadian variation points to a novel role for the signalosome

Gaspar

Howald

Popadin

et al. 2017

eLife

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“…We previously mentioned that GmCSN5 interacts with MiPM in the nucleus, as shown by BiFC. Whereas CSN5 occurs predominantly in the CSN complex in the nucleus, other CSN5 subcomplexes exist in the cytoplasm, whose roles and protein partners remain poorly defined (Gusmaroli et al, 2004 ; Wei et al, 2008 ; Schwechheimer and Isono, 2010 ; Pick and Bramasole, 2014 ). A previous study has demonstrated that HsCSN5 is involved in vesicle trafficking (Liu et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Meloidogyne incognita PASSE-MURAILLE (MiPM) Gene Encodes a Cell-Penetrating Protein That Interacts With the CSN5 Subunit of the COP9 Signalosome

et al. 2018

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The pathogenicity of phytonematodes relies on secreted virulence factors to rewire host cellular pathways for the benefits of the nematode. In the root-knot nematode (RKN) Meloidogyne incognita, thousands of predicted secreted proteins have been identified and are expected to interact with host proteins at different developmental stages of the parasite. Identifying the host targets will provide compelling evidence about the biological significance and molecular function of the predicted proteins. Here, we have focused on the hub protein CSN5, the fifth subunit of the pleiotropic and eukaryotic conserved COP9 signalosome (CSN), which is a regulatory component of the ubiquitin/proteasome system. We used affinity purification-mass spectrometry (AP-MS) to generate the interaction network of CSN5 in M. incognita-infected roots. We identified the complete CSN complex and other known CSN5 interaction partners in addition to unknown plant and M. incognita proteins. Among these, we described M. incognita PASSE-MURAILLE (MiPM), a small pioneer protein predicted to contain a secretory peptide that is up-regulated mostly in the J2 parasitic stage. We confirmed the CSN5-MiPM interaction, which occurs in the nucleus, by bimolecular fluorescence complementation (BiFC). Using MiPM as bait, a GST pull-down assay coupled with MS revealed some common protein partners between CSN5 and MiPM. We further showed by in silico and microscopic analyses that the recombinant purified MiPM protein enters the cells of Arabidopsis root tips in a non-infectious context. In further detail, the supercharged N-terminal tail of MiPM (NTT-MiPM) triggers an unknown host endocytosis pathway to penetrate the cell. The functional meaning of the CSN5-MiPM interaction in the M. incognita parasitism is discussed. Moreover, we propose that the cell-penetrating properties of some M. incognita secreted proteins might be a non-negligible mechanism for cell uptake, especially during the steps preceding the sedentary parasitic phase.

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“…A number of studies have suggested functions for CSN subunits in addition to the deneddylase activity of the complex, which resides in the CSN5 subunit [19,35,36]. Most of the other subunits have primarily structural roles within the holo-complex, although CSN1, CSN2 and CSN4 also contact CRL subunits [37][38][39].…”

Section: Introductionmentioning

confidence: 99%

The COP9 signalosome inhibits Cullin-RING E3 ubiquitin ligases independently of its deneddylase activity

Suisse¹,

Békés

Huang

et al. 2018

Fly

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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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Moonlighting and pleiotropy within two regulators of the degradation machinery: the proteasome lid and the CSN

Cited by 9 publications

References 60 publications

The genomic landscape of human cellular circadian variation points to a novel role for the signalosome

The genomic landscape of human cellular circadian variation points to a novel role for the signalosome

Meloidogyne incognita PASSE-MURAILLE (MiPM) Gene Encodes a Cell-Penetrating Protein That Interacts With the CSN5 Subunit of the COP9 Signalosome

The COP9 signalosome inhibits Cullin-RING E3 ubiquitin ligases independently of its deneddylase activity

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