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Alternative titles; symbolsCSN5JUN ACTIVATION DOMAIN-BINDING PROTEIN; JAB1SGN5MOV34 FAMILY, 38-KD MEMBERHGNC Approved Gene Symbol: COPS5Cytogenetic location: 8q1...

Alternative titles; symbols

  • CSN5
  • SGN5

HGNC Approved Gene Symbol: COPS5

Cytogenetic location: 8q13.1 Genomic coordinates (GRCh38): 8:67,043,078-67,062,132 (from NCBI)

▼ Description
COPS5 is a subunit of the COP9 signalosome (CSN), which phosphorylates target proteins, leading to their ubiquitination and degradation by the 26S proteasome. COPS5 functions as a receptor within the COP9 signalosome and binds substrate proteins (Bech-Otschir et al., 2001).

▼ Cloning and Expression
Using the more variable activation domain of JUN (165160) as bait in a yeast 2-hybrid system, Claret et al. (1996) identified JAB1. The JAB1 gene encodes a protein of 334 amino acids with a relative molecular mass of 37.5 kD. The N-terminal region of JAB1 shows 57% identity to the products of the open reading frame F37A4.5 of C. elegans and the S. pombe pad1+ gene, which was identified genetically as a coactivator of a subset of AP1 target genes. The JAB1 and pad1+ proteins are functionally interchangeable. They define a new group of coactivators that increase the specificity of target gene activation by AP1 proteins. The 1.5-kb JAB1 transcript was widely expressed. Immunofluorescence analysis indicated that JAB1 is a nuclear protein.

▼ Gene Family
Asano et al. (1997) identified JAB1 as a member of the MOV34 (PSMD7; 157970) family. They referred to JAB1 as the 38-kD MOV34 homolog.

▼ Gene Function
Using the yeast 2-hybrid system, Claret et al. (1996) found that JAB1 interacted with JUN and JUND (165162), but not with JUNB (165161) or v-jun. As a result, JAB1 selectively potentiated transactivation by only JUN or JUND. In vitro, JAB1 specifically stabilized complexes of JUN or JUND with AP1 sites and did not affect binding of either JUNB or v-jun. Amino acids 31 to 57 of JUN, which are absent in v-jun, contained the JAB1 interaction surface. JAB1 interacted with JUN and stimulated its activity in mammalian cells. Although JAB1 did not form a heterodimer with JUN or JUND, its effect on their DNA binding and transactivation abilities was analogous to the effect of the Extradenticle coactivator on homeodomain proteins of the Bithorax complex in Drosophila.

Bianchi et al. (2000) found that JAB1 interacts with the cytoplasmic domain of the beta-2 subunit of the alpha-L/beta-2 integrin LFA1 (153370/600065). Bianchi et al. (2000) found that JAB1 is present both in the nucleus and in the cytoplasm of cells and that a fraction of JAB1 colocalizes with LFA1 at the cell membrane. LFA1 engagement is followed by an increase of the nuclear pool of JAB1, paralleled by enhanced binding of c-Jun-containing AP1 complexes to their DNA consensus site and increased transactivation of an AP1-dependent promoter. Bianchi et al. (2000) suggested that signaling through the LFA1 integrin may affect JUN-driven transcription by regulating JAB1 nuclear localization. This represented a new pathway for integrin-dependent modulation of gene expression.

Using full-length macrophage migration inhibitory factor (MIF; 153620) as bait in a yeast 2-hybrid screen of a brain cDNA library, Kleemann et al. (2000) captured JAB1 as an interacting partner of MIF. By coimmunoprecipitation and pull-down experiments, Kleemann et al. (2000) confirmed the specific MIF-JAB1 association. Confocal microscopic analysis demonstrated that the MIF-JAB1 complex is localized in the cytosol near the peripheral plasma membrane, suggesting a potential connection between MIF and the integrin signaling pathways. Luciferase reporter and gel shift analyses showed that endogenous and exogenous MIF inhibited JAB1-induced AP1 transcriptional activity but did not interfere with nuclear factor kappa-B (NFKB; 164011) activity. Likewise, recombinant MIF inhibited JAB1-stimulated and tumor necrosis factor (TNF; 191160)-induced JNK (601158) activity. MIF also induced p27 (CDKN1B; 600778) expression and mirrored CDKN1B-mediated growth arrest through inhibition of JAB1-dependent degradation of CDKN1B. Mutational analysis indicated that a 16-residue MIF peptide spanning amino acids 50 through 65, including cys60, strongly competed with wildtype MIF for JAB1 binding. Kleemann et al. (2000) suggested that signaling through MIF-JAB1 is independent of a potential MIF receptor and noted that JAB1 is the only protein demonstrated to interact with MIF.

Using far Western and pull-down assays, Bech-Otschir et al. (2001) found that tetrameric p53 (TP53; 191170) interacted with purified human COP9 signalosome via JAB1. The signalosome subsequently phosphorylated p53, leading to p53 ubiquitination and degradation by the 26S proteasome. Phosphorylation of p53 was dependent on its binding to JAB1, and phosphorylation was a prerequisite for p53 ubiquitination and degradation.

Gemmill et al. (2002) isolated the Drosophila homolog of TRC8 (603046) and studied its function by genetic manipulations and a yeast 2-hybrid screen. Human and Drosophila TRC8 proteins localize to the endoplasmic reticulum. Loss of either Drosophila Trc8 or Vhl (608537) resulted in an identical ventral midline defect. Direct interaction between Trc8 and Vhl in drosophila was confirmed by GST-pull-down and coimmunoprecipitation experiments. Gemmill et al. (2002) found that in Drosophila, overexpression of Trc8 inhibited growth consistent with its presumed role as a tumor suppressor gene. Human JAB1 localization was dependent on VHL mutant status. Thus, the VHL, TRC8, and JAB1 proteins appear to be linked both physically and functionally, and all 3 may participate in the development of kidney cancer.

COP9 signalosome cleaves the ubiquitin-like protein NEDD8 (603171) from the CUL1 (603134) subunit of SCF ubiquitin ligases. Cope et al. (2002) found that the JAB1/MPN domain metalloenzyme (JAMM) motif in the JAB1/COPS5 subunit underlies the COP9 signalosome's NEDD8 isopeptidase activity. The JAMM motif consists of a his-X-his-X(10)-asp motif (where X indicates any residue) accompanied by an upstream glutamate. The JAMM motif is found in proteins from archaea, bacteria, and eukaryotes, including the RPN11 subunit of the 26S proteasome. Metal chelators and point mutations within the JAMM motif abolished COP9 signalosome-dependent cleavage of NEDD8 from CUL1, yet had little effect on COP9 signalosome complex assembly. Cope et al. (2002) proposed that JAMM isopeptidases play important roles in a variety of physiologic pathways.

Min et al. (2005) found that CSN interacted with CUL1 irrespective of its neddylation state. Addition of CAND1 (607727), which bound only unneddylated CUL1, inhibited binding of CUL1 to CSN and enhanced the deneddylase activity of CSN in vitro. Coexpression of specific CSN subunits revealed that CSN1 (GPS1; 601934), CSN2 (604508), CSN4 (616008), and CSN5 provided the minimal core CUL1-binding unit.

The marked box domain and adjacent region of the E2F1 gene (189971) are critical for the specificity of E2F1 apoptosis induction. Using the marked box domain of E2F1 in a yeast 2-hybrid screen of a human thymus cDNA library, Hallstrom and Nevins (2006) identified JAB1 as an E2F1 binding partner. JAB1 and E2F1 coexpression in rat embryonic fibroblasts synergistically induced apoptosis, coincident with the induction of p53 (191170) protein accumulation. In contrast, JAB1 did not synergize with E2F1 to promote cell cycle entry. Cells depleted of JAB1 were deficient for both E2F1-induced apoptosis and induction of p53 accumulation. Hallstrom and Nevins (2006) concluded that JAB1 is an essential cofactor for the apoptotic function of E2F1.

▼ Biochemical Features
Crystal Structure

Lingaraju et al. (2014) presented the crystal structure of the entire 350-kD human CSN holoenzyme at 3.8-angstrom resolution, detailing the molecular architecture of the complex. CSN has 2 organizational centers: a horseshoe-shaped ring created by its 6 proteasome lid-CSN-initiation factor-3 domain proteins, and a large bundle formed by the carboxy-terminal alpha-helices of every subunit. CSN5 and its dimerization partner, CSN6 (COPS6; 614729), are intricately embedded at the core of the helical bundle. In the substrate-free holoenzyme, CSN5 is autoinhibited, which precludes access to the active site. Lingaraju et al. (2014) found that neddylated cullin-RING E3 ubiquitin ligase binding to CSN is sensed by CSN4, and communicated to CSN5 with the assistance of CSN6, resulting in activation of the deneddylase.

▼ Mapping
Hartz (2004) mapped the COPS5 gene to chromosome 8q13.2 based on an alignment of the COPS5 sequence (GenBank U65928) with the genomic sequence.

▼ Animal Model
Tomoda et al. (2004) found that Jab1 null mouse embryos died soon after implantation. Mutant embryonic cells, which lacked other Cop9 signalosome components, expressed higher levels of p27, p53 (191170), and cyclin E (123837), resulting in impaired proliferation and accelerated apoptosis. Jab1 heterozygous mice were healthy and fertile but smaller than their wildtype littermates. Heterozygous mouse embryonic fibroblasts proliferated poorly, showed an inefficient downregulation of p27 during G1, and were delayed in the progression from G0 to S phase compared with wildtype cells. The levels of cyclin E and deneddylated Cul1 were unchanged and p53 was not induced in heterozygous mutant cells. Tomoda et al. (2004) concluded that JAB1 controls cell cycle progression and cell survival by regulating multiple signaling pathways.

Tags: 8q13.1