Targeting the COP9 signalosome for cancer therapy

The COP9 signalosome(CSN)is a highly conserved protein complex composed of 8 subunits(CSN1 to CSN8).The individual subunits of the CSN play essential roles in cell proliferation,tumorigenesis,cell cycle regulation,DNA damage repair,angiogenesis,and microenvironmental homeostasis.The CSN complex has an intrinsic metalloprotease that removes the ubiquitin-like activator NEDD8 from cullin-RING ligases(CRLs).Binding of neddylated CRLs to CSN is sensed by CSN4 and communicated to CSN5 with the assistance of CSN6,thus leading to the activation of deneddylase.Therefore,CSN is a crucial regulator at the intersection between neddylation and ubiquitination in cancer progression.Here,we summarize current understanding of the roles of individual CSN subunits in cancer progression.Furthermore,we explain how the CSN affects tumorigenesis through regulating transcription factors and the cell cycle.Finally,we discuss individual CSN subunits as potential therapeutic targets to provide new directions and strategies for cancer therapy.

The COP9 Signalosome Controls Adipocyte Differentiation by Regulating CHOP Protein Stability

Obesity is a serious health problem of our time. Dysfunction of adipogenesis, the differentiation of adipocytes, is a hallmark of obesity. Therefore here we investigate the role of the COP9 signalosome and of CHOP in the differentiation of LiSa-2 preadipocytes.

Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5

Programmed cell death-1(PD-1)/programmed cell death ligand-1(PD-L1)blocking therapy has become a major pillar of cancer immunotherapy.Compared with antibodies targeting,small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed.Here we identified berberine(BBR),a proven anti-inflammation drug,as a negative regulator of PDL1 from a set of traditional Chinese medicine(TCM)chemical monomers.BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells.In addition,BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumorinfiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells(MDSCs)and regulatory T-cells(Tregs).BBR triggered PD-L1 degradation through ubiquitin(Ub)/proteasome-dependent pathway.Remarkably,BBR selectively bound to the glutamic acid76 of constitutive photomorphogenic-9 signalosome 5(CSN5)and inhibited PD-1/PD-L1 axis through its deubiquitination activity,resulting in ubiquitination and degradation of PD-L1.Our data reveals a previously unrecognized antitumor mechanism of BBR,suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.

CSN1 inhibits c-Jun phosphorylation and down-regulates ectopic expression of JNK1

CSN1 is a component of the COP9 signalosome(CSN),a conserved protein complex with pleiotropic functions in many organs and cell types.CSN regulates ubiquitinproteasome dependent protein degradation via the deneddylation and the associated deubiquitination activities.In addition,CSN associates with protein kinases and modulates cell signaling,particularly the activator protein 1(AP-1)pathway.We have shown previously that CSN1 suppresses AP-1 transcription activity and inhibits ultraviolet(UV)and serum activation of c-fos expression.Here we show that CSN1 can inhibit phosphorylation of proto-oncogene c-Jun product and repress c-Jun dependent transcription.Further,CSN1 dramatically downregulates ectopic expression of c-Jun N-terminal kinase 1(JNK1)in cultured cells.The decline in JNK1 is not caused by excessive proteolysis or by 3′UTR-dependent mRNA instability,but by CSN1-dependent repression of one or multiple steps in transcriptional and posttranscriptional mechanisms.Thus,in contrast to CSN5/Jab1,which promotes AP-1 activity,CSN1 displays a negative effect on the AP-1 pathway.Finally,we discuss about the dynamic equilibrium of the CSN complexes in regulation of the AP-1 pathway.

Higher-order assemblies in immune signaling:supramolecular complexes and phase separation

Signaling pathways in innate and adaptive immunity play vital roles in pathogen recognition and the functions of immune cells.Higher-order assemblies have recently emerged as a central principle that governs immune signaling and,by extension,cellular communication in general.There are mainly two types of higher-order assemblies:1)ordered,solid-like large supramolecular complexes formed by stable and rigid protein-protein interactions,and 2)liquid-like phase-separated condensates formed by weaker and more dynamic intermolecular interactions.This review covers key examples of both types of higher-order assemblies in major immune pathways.By placing emphasis on the molecular structures of the examples provided,we discuss how their structural organization enables elegant mechanisms of signaling regulation.