JAB1 deletion in oligodendrocytes causes senescence-induced inflammation and neurodegeneration in mice.

Oligodendrocytes are the primary target of demyelinating disorders, and progressive neurodegenerative changes may evolve in the CNS. DNA damage and oxidative stress are considered key pathogenic events, but the underlying molecular mechanisms remain unclear. Moreover, animal models do not fully recapitulate human diseases, complicating the path to effective treatments. Here we report that mice with cell-autonomous deletion of the nuclear COP9 signalosome component CSN5 (JAB1) in oligodendrocytes develop DNA damage and defective DNA repair in myelinating glial cells. Interestingly, oligodendrocytes lacking JAB1 expression underwent a senescence-like phenotype that fostered chronic inflammation and oxidative stress. These mutants developed progressive CNS demyelination, microglia inflammation, and neurodegeneration, with severe motor deficits and premature death. Notably, blocking microglia inflammation did not prevent neurodegeneration, whereas the deletion of p21CIP1 but not p16INK4a pathway ameliorated the disease. We suggest that senescence is key to sustaining neurodegeneration in demyelinating disorders and may be considered a potential therapeutic target.

COPS8 in cutaneous melanoma: an oncogene that accelerates the malignant development of tumor cells and predicts poor prognosis.

This study aimed to investigate the roles of COP9 signalosome subunit 8 (COPS8) and its underlying mechanism in cutaneous melanoma. Bioinformatics tools were utilized to analyze the expression of COPS8 in cutaneous melanoma, while Kaplan-Meier analysis was employed to assess the correlation between COPS8 and patients' overall survival. The proliferation, migration, and invasion of cells were estimated by CCK8, colony formation, and Transwell assays. Western blot was used to check the expression of epithelial-mesenchymal transition (EMT)-related proteins. Results showed that COPS8 was up-regulated and predicted a poor clinical outcome for cutaneous melanoma patients. Knockdown of COPS8 inhibited cutaneous melanoma cell proliferation, migration and invasion, whereas overexpression of COPS8 resulted in the opposite outcomes. The up-regulation of E-cadherin and down-regulation of N-cadherin, vimentin, and snail were caused by silencing COPS8 while their expression showed contrary trends in cells with overexpressed COPS8. Collectively, COPS8 is up-regulated and promotes cutaneous melanoma progression via regulating EMT.

Knockdown of COPS3 inhibits the progress of prostate cancer through reducing phosphorylated p38 MAPK expression and impairs the epithelial-mesenchymal transition process.

BACKGROUND: The amplification of gene COPS3 is closely related to the development of osteosarcoma and hepatocellular carcinoma. However, the effects of COPS3 on prostate cancer (PCa) are poorly understood. METHODS: In this study, the protein expression of COPS3 in PCa tissues, adjacent normal tissues, and bone metastasis tissues of PCa was analyzed by immunohistochemistry. Furthermore, cell proliferation, colony formation, migration, and invasion assay were performed in 22rv1 and PC-3 cells after knocking down COPS3 by small interfering RNAs. Furthermore, we performed western blot analysis to explore the potential mechanisms underlying it. RESULTS: This study found that the overall survival of the COPS3 high-expression group was significantly shorter than the low-expression group. This study discovered that the protein expression of COPS3 in PCa tissues was higher than that in the matched nontumor prostate tissues. In addition, tissues from bone metastasis of PCa had a high percentage of overexpressing COPS3. After knockdown of the COPS3 gene in 22rv1 and PC3 cells, two classic human PCa cell lines which had a high level of COPS3, the abilities of migration, invasion, and proliferation were inhibited. Finally, protein levels of phosphorylated P38 mitogen-activated protein kinase (MAPK) and N-cadherin were significantly decreased after knocking down the expression of COPS3, and the protein levels of E-cadherin were significantly increased. CONCLUSIONS: In conclusion, COPS3 may be closely related to the progress of PCa. Knockdown of COPS3 inhibited the progress of PCa through reducing the levels of phosphorylated P38 MAPK and impaired the epithelial-mesenchymal transition process.

Renal COP9 Signalosome Deficiency Alters CUL3-KLHL3-WNK Signaling Pathway.

BACKGROUND: The familial hyperkalemic hypertension (FHHt) cullin 3 (CUL3) mutant does not degrade WNK kinases normally, thereby leading to thiazide-sensitive Na-Cl cotransporter (NCC) activation. CUL3 mutant (CUL3Δ9) does not bind normally to the COP9 signalosome (CSN), a deneddylase involved in regulating cullin-RING ligases. CUL3Δ9 also caused increased degradation of the CUL3-WNK substrate adaptor kelch-like 3 (KLHL3). Here, we sought to determine how defective CSN action contributes to the CUL3Δ9 phenotype. METHODS: The Pax8/LC1 mouse system was used to generate mice in which the catalytically active CSN subunit, Jab1, was deleted only along the nephron, after full development (KS-Jab1-/-). RESULTS: Western blot analysis demonstrated that Jab1 deletion increased the abundance of neddylated CUL3. Moreover, total CUL3 expression was reduced, suggesting decreased CUL3 stability. KLHL3 was almost completely absent in KS-Jab1-/- mice. Conversely, the protein abundances of WNK1, WNK4, and SPAK kinases were substantially higher. Activation of WNK4, SPAK, and OSR1 was indicated by higher phosphorylated protein levels and translocation of the proteins into puncta, as observed by immunofluorescence. The ratio of phosphorylated NCC to total NCC was also higher. Surprisingly, NCC protein abundance was low, likely contributing to hypokalemia and Na+ and K+ wasting. Additionally, long-term Jab1 deletion resulted in kidney damage. CONCLUSIONS: Together, the results indicate that deficient CSN binding contributes importantly to the FHHt phenotype. Although defective CUL3Δ9-faciliated WNK4 degradation likely contributes, dominant effects on KLHL3 may be a second factor that is necessary for the phenotype.

Genome-wide analysis of gene expression profiling revealed that COP9 signalosome is essential for correct expression of Fe homeostasis genes in Arabidopsis.

In plant cells, either excess or insufficient iron (Fe) concentration triggers stress responses, therefore it is strictly controlled. Proteasome-mediated degradation through ubiquitination of Fe homeostasis proteins has just become the focus of research in recent years. Deactivating ubiquitin ligases, COP9 signalosome has a central importance in the translational control of various stress responses. The aim of the study was to investigate COP9 signalosome in Fe deficiency response of Strategy I plants. In silico analysis of a set of Fe-deficiency-responsive genes was conducted against the transcriptome of Arabidopsis csn mutant lines using Genevestigator software. Induced and suppressed genes were clustered in a hierarchical way and gene ontology enrichment categories were identified. In wild-type Arabidopsis, CSN genes did not respond to iron deficiency. In csn mutant lines, under Fe-sufficient conditions, hundreds of Fe-deficiency-responsive genes were misregulated. Among the ones previously characterized for their physiological roles under Fe deficiency IRT1, NAS4, BTS, NRAMP1 were down-regulated while AHA2, MTP8, FRD3 were up-regulated. Unexpectedly, from those which were regulated in opposite ways, some had been repeatedly shown to be tightly co-regulated by the same transcription factor, FIT. Two proteins from DELLA family, which were reported to interact with FIT to repress its downstream, were found to be strikingly repressed in csn mutants. Overall, the study underlined that the absence of a functional CSN greatly impacted the regulation of Fe homeostasis-related genes, in a manner which cannot be explained simply by the induction of the master transcription factor, FIT. Correct expression of Fe deficiency-responsive genes requires an intact COP9 signalosome in Arabidopsis.