The ubiquitin-proteasome pathway is responsible for the degradation of most cellular proteins in eukaryotes.It regulates almost all cellular activities, including cell proliferation, differentiation, apoptosis, gene transcription, and DNA repair.The dysfunction of the ubiquitin-proteasome pathway is associated with the pathogenesis of numerous human diseases, including cancer and neurodegenerative diseases.The marketed proteasome inhibitors have been successfully used to treat multiple myeloma and mantle cell lymphoma.Furthermore, novel inhibitors against the components of the ubiquitin-proteasome pathway are under developed and exhibit promising therapeutic effects in vivo.This paper will briefly introduce the progress on the drug discovery related to the ubiquitin-proteasome pathway.

Objective To discover a novel long noncoding RNA YLL066W-B (referred to as YLB), whose expression can be regulated by a ubiquitin ligases E3, Huwel/Tom1, and further investigate the regulatory effects of YLB on expression of multiple subtelomeric genes. Methods Yeast strains (including Tom1△, YLB-HA, HA-YLB, pYES2-HA-YLB and YLB△) were constructed according to the principle of PCR-based tagging of yeast genes. The effects of Tom1 deletion on gene expression were analyzed by real-time PCR and DNA microarray. The protein levels were detected by Western blot. We further performed quantitative real time-PCR to analyze the inlfuence of YLB on expression of multiple subtelomerical genes.Results We found that deletion of Tom1 in yeast could affect the expression of multiple genes and greatly up-regulated the expression of YLB, which is implicated in cell cycle regulation. By analyzing its nucleotide sequence(171 bp)and detecting protein expression, we speculate that the transcriptional product of YLB is a long noncoding RNA (lncRNA). Although YLB is not homologous to any protein-encoding sequences by NCBI blast, it is homologous to the upstream or downstream regions of the open reading frame of several subtelomerically-encoded genes, including those from pau family and DNA helicase Yrf family. Thus, it is possible that YLB is involved in the regulation of these subtelomerically-encoded genes. Accordingly, deletion of YLB markedly up-regulated the mRNA levels of Yrf1-4, pau4 and pau22, whereas over-expression of YLB greatly down-regulated their expression.Conclusion We have discovered the novel lncRNA YLB. The expression of YLB could be negatively regulated by Tom1, and YLB could regulate the expression of multiple subtelomeric genes.

Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been explored. Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) target genes, including fibroblast growth factor (FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2e1-null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2E1 and to serve as PPARα agonists, thus explaining how CYP2E1 deficiency causes hepatic PPARα activation through increasing cellular levels of endogenous PPARα agonists. Translationally, a CYP2E1 inhibitor was found to activate the PPARα-FGF21-beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Ppara-null mice. The present results establish a metabolic crosstalk between PPARα and CYP2E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism.