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Results for “COP9 Signalosome Complex”

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PubMed2005

Growth suppression induced by the TRC8 hereditary kidney cancer gene is dependent upon JAB1/CSN5.

TRC8 encodes an E3-ubiquitin ligase disrupted in a family with hereditary renal cell carcinoma (RCC). We previously reported that Drosophila Trc8 (DTrc8) overexpression inhibits growth and that human and fly proteins interact with with the COP9 signalosome (CSN) subunit JAB1/CSN5. However, further mechanistic evidence linking DTrc8 growth suppression to CSN5 was lacking. Here, we show that haploinsufficiency of CSN5, or a T100I point mutation (CSN5(3)), relieved growth suppression by DTrc8, whereas CSN5(1) (E160V) and CSN5(2) (G147D) mutations had no effect. The strength of yeast two-hybrid interactions between DTrc8 and CSN5 were in complete agreement with the observed phenotypes. DTrc8 overexpression resulted in elevated levels of CSN5 and CSN7, but had no effect on NEDD8-modified Cul-1. In contrast to CSN5, heterozygosity for CSN4null had no effect on the DTrc8 phenotype. We also looked for genetic interactions between DTrc8 and other MPN domain proteins in the CSN and 26S proteasome lid. CSN6 haploinsufficiency restored growth, whereas reduction of proteasome subunits RPN8 or RPN11 had no effect. DTrc8 expression increased the level of digitonin-extractable CSN complex, consistent with elevated levels of CSN5 and 7. Our genetic results confirm that DTrc8-induced growth suppression is CSN5 (and CSN6) dependent. While there was no obvious influence on CSN deneddylation activity, the increase in CSN subunits and holocomplex suggests that TRC8 modulates signalosome levels or compartmentalization.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Arabidopsis jasmonate signaling pathway.

Jasmonates control defense gene expression and male fertility in the model plant Arabidopsis thaliana. In both cases, the involvement of the jasmonate pathway is complex, involving large-scale transcriptional reprogramming. Additionally, jasmonate signaling is hard-wired into the auxin, ethylene, and salicylate signal networks, all of which are under intense investigation in Arabidopsis. In male fertility, jasmonic acid (JA) is the essential signal intervening both at the level of anther elongation and in pollen dehiscense. A number of genes potentially involved in jasmonate-dependent anther elongation have recently been discovered. In the case of defense, at least two jasmonates, JA and its precursor 12-oxo-phytodienoic acid (OPDA), are necessary for the fine-tuning of defense gene expression in response to various microbial pathogens and arthropod herbivores. However, only OPDA is required for full resistance to some insects and fungi. Other jasmonates probably affect yet more physiological responses. A series of breakthroughs have identified the SKP/CULLIN/F-BOX (SCF), CORONATINE INSENSITIVE (COI1) complex, acting together with the CONSTITUTIVE PHOTOMORPHOGENIC 9 (COP9) signalosome, as central regulatory components of jasmonate signaling in Arabidopsis. The studies, mostly involving mutational approaches, have paved the way for suppressor screens that are expected to further extend our knowledge of jasmonate signaling. When these and other new mutants affecting jasmonate signaling are characterized, new nodes will be added to the Arabidopsis Jasmonate Signaling Pathway Connections Map, and the lists of target genes regulated by jasmonates in Arabidopsis will be expanded.

Arabidopsis↗

PubMed2002

Ubiquitin system: JAMMing in the name of the lid.

The isopeptide bonds formed by ubiquitin or its relatives are cleaved by hydrolases with active site cysteines. Recent studies have revealed that similar metalloprotease motifs--JAMMs--in the Rpn11 subunit of the 26S proteasome lid and in the Csn5 subunit of the COP9 signalosome are involved in deubiquitination and deneddylation, respectively.

Metalloendopeptidases↗

PubMed2005

Loss of the CONSTITUTIVE PHOTOMORPHOGENIC9 signalosome subunit 5 is sufficient to cause the cop/det/fus mutant phenotype in Arabidopsis.

The COP9 signalosome (CSN) was originally identified based on the constitutively photomorphogenic/de-etiolated/fusca (cop/det/fus) mutants from Arabidopsis thaliana. CSN is evolutionary conserved, and its subunit 5 (CSN5) mediates the deconjugation of NEDD8 from the cullin subunit of E3 ubiquitin ligases (deneddylation). Here, we report on Arabidopsis mutants deficient in CSN5 function. We show that these mutants are phenotypically indistinguishable from the previously described cop/det/fus mutants of other CSN subunits. However, we also show that these mutants retain the CSN complex (lacking CSN5), and this finding is in contrast with the previously described CSN subunit mutants, which lack the CSN complex. We therefore conclude that loss of CSN5 as part of CSN is sufficient to cause the cop/det/fus mutant phenotype. Furthermore, we show that mutants defective in CSN5 as well as mutants defective in CSN are unable to deneddylate the Arabidopsis cullins AtCUL1, AtCUL3A, and AtCUL4. Because these are representative cullin subunits of the three cullin-containing E3 families present in Arabidopsis, we postulate that the cop/det/fus mutant phenotype may be the result of the defects caused by impaired CSN5-dependent deneddylation of cullin-containing E3s.

Arabidopsis↗

PubMed2001

Dissection of the light signal transduction pathways regulating the two early light-induced protein genes in Arabidopsis.

The expression of light-regulated genes in plants is controlled by different classes of photoreceptors that act through a variety of signaling molecules. During photomorphogenesis, the early light-induced protein (Elip) genes are among the first to be induced. To understand the light signal transduction pathways that regulate Elip expression, the two Elip genes, Elip1 and Elip2, in Arabidopsis were studied, taking advantage of the genetic tools available for studying light signaling in Arabidopsis. Using two independent quantitative reverse transcriptase-PCR techniques, we found that red, far-red, and blue lights positively regulate expression of the Elip genes. Phytochrome A and phytochrome B are involved in this signaling. The cryptochrome or phototropin photoreceptors are not required for blue-light induction of either Elip gene, suggesting the involvement of an additional, unidentified, blue-light receptor. Although the COP9 signalosome, a downstream regulator, is involved in dark repression of both Elips, Elip1 and Elip2 show different expression patterns in the dark. The transcription factor HY5 promotes the light induction of Elip1, but not Elip2. A defect in photosystem II activity in greening of hy5 seedlings may result from the loss of Elip1. Heat shock positively controlled Elip1 and Elip2 in a light-independent fashion. This induction is independent of HY5, indicating that heat shock and light activate transcription of the Elip genes through independent pathways.

Arabidopsis↗

PubMed2007

Dysregulation of the ubiquitin-proteasome system by curcumin suppresses coxsackievirus B3 replication.

Curcumin (diferuloylmethane), a natural polyphenolic compound extracted from the spice turmeric, has been reported to have anti-inflammatory, antioxidant, and antiproliferative properties by modulating multiple cellular machineries. It inhibits several intracellular signaling pathways, including the mitogen-activated protein kinases (MAPKs), casein kinase II (CKII), and the COP9 signalosome (CSN), in various cell types. It has also been recently demonstrated that exposure to curcumin leads to the dysregulation of the ubiquitin-proteasome system (UPS). Coxsackievirus infection is associated with various diseases, including myocarditis and dilated cardiomyopathy. In searching for new antiviral agents against coxsackievirus, we found that treatment with curcumin significantly reduced viral RNA expression, protein synthesis, and virus titer and protected cells from virus-induced cytopathic effect and apoptosis. We further demonstrated that reduction of viral infection by curcumin was unlikely due to inhibition of CVB3 binding to its receptors or CVB3-induced activation of MAPKs. Moreover, gene silencing of CKII and Jab1, a component of CSN, by small interfering RNAs did not inhibit the replication of coxsackievirus, suggesting that the antiviral action of curcumin is independent of these pathways. Finally, we showed that curcumin treatment reduced both the 20S proteasome proteolytic activities and the cellular deubiquitinating activities, leading to increased accumulation of ubiquitinated proteins and decreased protein levels of free ubiquitin. We have recently demonstrated that the UPS-mediated protein degradation and/or modification plays a critical role in the regulation of coxsackievirus replication. Thus, our results suggest an important antiviral effect of curcumin wherein it potently inhibits coxsackievirus replication through dysregulation of the UPS.

Apoptosis↗