CSN5

UniProt ID: A0A0B4KHM2
Organism: Drosophila melanogaster
Review Status: DRAFT
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Gene Description

CSN5 (also called Jab1) is the catalytic subunit of the Drosophila COP9 signalosome, an eight-subunit complex related to the 26S proteasome lid. Its MPN domain carries a JAMM metal-binding motif (His-x-His...Asp) that forms the active site of the signalosome's NEDD8 isopeptidase, which removes NEDD8 from the cullin subunits of cullin-RING ubiquitin ligases such as SCF complexes. CSN5 has no isopeptidase activity on its own; activity requires assembly with the other signalosome subunits. By resetting cullin neddylation, the complex controls ubiquitin-dependent turnover of cell-cycle and signalling proteins, for example Cyclin E in early oogenesis. CSN5 is found in the cytoplasm and the nucleus. Loss of CSN5 is lethal and disrupts oogenesis, germline stem cell maintenance, photoreceptor differentiation and glial migration, and hemocyte homeostasis; these are downstream consequences of altered cullin-RING ligase activity. The gene encodes two products, PA (327 aa) and PB (325 aa); PB lacks two residues (Gly278-Arg279) outside the MPN domain and keeps the complete catalytic region.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005634 nucleus
IEA
GO_REF:0000044 		ACCEPT
Summary: CSN5 occurs in both nuclear and cytoplasmic pools; nucleus is the appropriate compartment-level term for the PB product.
Reason: The reviewed same-gene PA entry (Q9XZ58) records nuclear and cytoplasmic localization, and FlyBase records an IDA for nuclear periphery (a part of the nucleus) from larval hemocyte immunostaining (PMID:17295838). PB is identical to PA except for two residues outside the MPN domain, so compartment-level localization transfers. Nucleus is as precise as is warranted across tissues; the nuclear-periphery observation is tissue-specific and was not tested on PB. The SubCell mapping is consistent with the conserved COP9 signalosome distribution.
Supporting Evidence:
file:DROME/CSN5/CSN5-reference-Q9XZ58-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305|PubMed:10531038}. Nucleus
file:DROME/CSN5/CSN5-bioinformatics/RESULTS.md
The MPN domain 52–189 and JAMM motif 135–148 are completely retained, including His135, His137 and Asp148.
GO:0005737 cytoplasm
IEA
GO_REF:0000044 		ACCEPT
Summary: CSN5 is cytoplasmic as well as nuclear; the same-gene PA product has direct cytoplasmic localization evidence and PB shares its sequence.
Reason: FlyBase holds IDA cytoplasm annotations for the PA product (PMID:11779478, CSN5 accumulation in the developing optic-lobe neuropil, i.e. in R-cell axons; PMID:17295838), and PAINT propagates cytoplasm (is_active_in) from node PTN000045369, the CSN5 clade containing this gene. PB differs from PA only by the Gly278-Arg279 deletion outside the MPN domain.
Supporting Evidence:
PMID:11779478
the JAB1/CSN5 subunit of the COP9 signalosome complex is expressed in R cells, accumulates in the developing optic lobe neuropil
file:DROME/CSN5/CSN5-reference-Q9XZ58-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305|PubMed:10531038}. Nucleus
file:DROME/CSN5/CSN5-bioinformatics/RESULTS.md
The 325-residue CSN5-PB/A0A0B4KHM2 sequence matches 325 of 327 residues of reviewed PA/Q9XZ58, lacking Gly278 and Arg279 outside the MPN domain.
GO:0008233 peptidase activity
IEA
GO_REF:0000002 		MODIFY
Summary: Correct but too general; the specific activity is metal-dependent NEDD8 isopeptidase (deNEDDylase) activity on cullins, supplied by the CSN5 JAMM site within the COP9 signalosome.
Reason: The JAMM/MPN+ InterPro mapping to generic peptidase activity is right in kind, since JAMM proteins are metalloisopeptidases. For CSN5 the substrate is established. Metal chelators and JAMM point mutations abolish CSN-dependent removal of Nedd8 from Cul1, and fly csn5 mutants fail to deneddylate Cullin1 in the ovary. FlyBase already holds an IDA for GO:0140758 on the PA product (PMID:12737805), and PAINT propagates deNEDDylase activity from the CSN5 clade node PTN000045369. PB keeps His135, His137 and Asp148. The activity is expressed only in the assembled complex, so the core function records it with contributes_to_molecular_function and the COP9 signalosome.
Supporting Evidence:
PMID:12183637
Metal chelators and point mutations within JAMM abolished CSN-dependent cleavage of Nedd8 from Cul1, yet had little effect on CSN complex assembly.
PMID:12737805
we show that the CSN acts during Drosophila oogenesis to remove Nedd8 from Cullin1
file:DROME/CSN5/CSN5-reference-Q9XZ58-uniprot.txt
In the complex, it probably acts as the catalytic center that mediates the cleavage of Nedd8 from cullins. It however has no metalloprotease activity by itself and requires the other subunits of the CSN complex.
file:DROME/CSN5/CSN5-bioinformatics/RESULTS.md
The MPN domain 52–189 and JAMM motif 135–148 are completely retained, including His135, His137 and Asp148.

Core Functions

Supplies the JAMM metal-dependent catalytic center of the COP9 signalosome's NEDD8 isopeptidase, which removes NEDD8 from cullins of cullin-RING ubiquitin ligases. It is active only within the assembled complex.

Directly Involved In:
protein deneddylation
Cellular Locations:
nucleus cytoplasm
In Complex:
COP9 signalosome
Supporting Evidence:
  • PMID:12183637
    Metal chelators and point mutations within JAMM abolished CSN-dependent cleavage of Nedd8 from Cul1, yet had little effect on CSN complex assembly.
  • PMID:12737805
    we show that the CSN acts during Drosophila oogenesis to remove Nedd8 from Cullin1
  • file:DROME/CSN5/CSN5-reference-Q9XZ58-uniprot.txt
    In the complex, it probably acts as the catalytic center that mediates the cleavage of Nedd8 from cullins. It however has no metalloprotease activity by itself and requires the other subunits of the CSN complex.
  • file:DROME/CSN5/CSN5-bioinformatics/RESULTS.md
    The MPN domain 52–189 and JAMM motif 135–148 are completely retained, including His135, His137 and Asp148.

References

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Suggested Questions for Experts

Q: Do the PA and PB isoforms (which differ only at Gly278-Arg279) differ in expression, for example in the testis-specific COP9 signalosome variant (ComplexPortal CPX-7964), or are they functionally interchangeable?

External Prediction Reviews

These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.

ProtNLM2 External predictions

View prediction review YAML · CSN5-protnlm-predictions-review.yaml · Review status: COMPLETE

CSN5 has a supported signalosome catalytic role; synaptic-vesicle localization rests on a single mammalian ortholog study and is unverified for the fly PB product.

Source documents: genes/DROME/CSN5/CSN5-protnlm-source.json · genes/DROME/CSN5/CSN5-bioinformatics/RESULTS.md

Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.

GO:0008021 synaptic vesicle GO_CC
UNC — Uncertain Review score: 1/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08 · file:DROME/CSN5/CSN5-protnlm-source.json
Review rationale: The target is a near-identical CSN5 splice product retaining the complete JAMM catalytic domain, and primary evidence establishes its COP9 deneddylation mechanism. The only experimental support for a synaptic-vesicle location in this ortholog group is a human COPS5 annotation from a mammalian study of the CSN complex in neuroblastoma cells and brain synaptosomes, whose abstract describes CSN4 binding and a role in synaptic protein stability rather than CSN5 residence in vesicles, and whose full text is not cached. Insects have no reported CSN5 synaptic localization, and no PAINT or curated phylogenetic transfer carries this term to the fly protein. The fly gene review records only nucleus and cytoplasm locations. The donor label from Xenopus Q6GLM9 is therefore not validated for the target, and no fly evidence refutes it. The term is absent from the GOA of both fly CSN5 products.
Supporting Evidence:
  • file:DROME/CSN5/CSN5-bioinformatics/RESULTS.md: "The MPN domain 52–189 and JAMM motif 135–148 are completely retained, including His135, His137 and Asp148."
  • PMID:12183637: "The Jab1/MPN domain metalloenzyme (JAMM) motif in the Jab1/Csn5 subunit was found to underlie CSN's Nedd8 isopeptidase activity."
  • PMID:21102408: "TA binds CSN4 and the synaptic regulator snapin in neuroblastoma cells and in brain synaptosomes."

Deep Research

Falcon

(CSN5-deep-research-falcon.md)

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FlyBase

(CSN5-deep-research-flybase.md)
FlyBase gene description for CSN5 (DROME) FlyBase

FlyBase gene description for CSN5 (DROME)

COP9 signalosome subunit 5 (CSN5) encodes the subunit 5 of the COP9 signalosome (CSN). The CSN plays a central role in the regulation of E3-cullin RING ubiquitin ligases. The product of CSN5 is an isopeptidase that deNEDDylates the cullin subunit of E3-cullin RING ubiquitin ligases.

📚 Additional Documentation

Notes

(CSN5-notes.md)

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Bioinformatics Results

(RESULTS.md)

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📄 View Raw YAML

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