Loss of CD4 T cell help correlates with virus persistence during acute hepatitis C (HCV) infection, but the underlying mechanism(s) remain unknown. We developed a combined proliferation/intracellular cytokine staining assay to monitor expansion HCV-specific cells and helper cytokines expression patterns infections different outcomes. demonstrate that resolving HCV is characterized by strong Th1/Th17 responses specific IL-21-producing increased IL-21 levels in plasma. In contrast, viral was...

ABSTRACT The majority of acute hepatitis C virus (HCV) infections progress to chronicity and progressive liver damage. Alpha interferon (IFN-α) antiviral therapy achieves the highest rate success when IFN-α is administered early during phase, but underlying mechanisms are unknown. We used a panel major histocompatibility complex class I tetramers monitor phenotypic functional signatures HCV-specific T cells HCV infection with different outcomes IFN therapy. demonstrate that spontaneous...

Research Article29 May 2018Open Access Source DataTransparent process The AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation-associated cachectic muscle wasting Derek T Hall Department of Biochemistry, McGill University, Montreal, QC, Canada Rosalind and Morris Goodman Cancer Centre, Search for more papers by this author Takla Griss Physiology, Jennifer F Ma Brenda Janice Sanchez Jason Sadek Anne Marie K Tremblay Souad Mubaid Amr Omer...

Ubiquitin-dependent proteolysis is activated in skeletal muscle atrophying response to various catabolic stimuli. Previous studies have demonstrated activation of ubiquitin conjugation. Because ubiquitination can also be regulated by deubiquitinating enzymes, we used degenerate oligonucleotides derived from conserved sequences the ubiquitin-specific protease (UBP) family enzymes RT-PCR with RNA amplify putative enzymes. We identified USP19, a 150-kDa enzyme that widely expressed tissues...

p27(Kip1) is a cyclin-dependent kinase inhibitor that regulates the G(1)/S transition. Increased degradation of associated with cellular transformation. Previous work demonstrated ubiquitin ligases KPC1/KPC2 and SCF(Skp2) ubiquitinate in G(1) early S, respectively. The regulation these remains unclear. We report here USP19 deubiquitinating enzyme interacts stabilizes KPC1, thereby modulating levels cell proliferation. Cells depleted by RNA interference exhibited an inhibition proliferation,...

Hepatitis C virus (HCV) is a worldwide health problem. No vaccine available against this pathogen and therapeutic treatments currently in use are of limited efficacy. In the present study, immunogenicity candidate CIGB-230, based on mixture pIDKE2, plasmid expressing HCV structural antigens, with recombinant core protein, Co.120, was evaluated. CIGB-230 administered by intramuscular injection weeks 0, 4, 8, 12, 16 20 to 15 HCV-chronically infected individuals, non-responders previous...

Theubiquitin-proteasome system plays an important role in spermatogenesis. However, the functions of deubiquitinating enzymes this process remain poorly characterized. We previously showed that enzyme USP2 is induced late elongating spermatids. To identify its function, we generated mice lacking USP2. Usp2 −/− appeared normal, and weights major organs, including testis, did not differ from wild type (Usp2 +/+). although numbers testicular spermatids epididymal spermatozoa were normal males,...

Significance During chronic viral infection, CD8 + T cells are gradually deprived of their principal effector functions and irreversibly loose plasticity to develop into memory populations, precluding the establishment long-lasting protective immunity. Relevant host-derived factors directing this T-cell exhaustion process have remained elusive. Growing evidence suggests that cytokine milieu dramatically impacts outcome infection. However, it is unclear if cytokines directly promote and, so,...

Abstract Liver fibrosis is a global health problem. IL-17A has proven profibrogenic properties in liver disease making it an interesting therapeutic target. regulated by RORγt and produced Th17 CD4+ γδ-T cells. We hypothesized that blocking production will limit progression reducing recruitment of inflammatory Herein, we tested the potential 2 novel inverse agonists (2,3 derivatives 4,5,6,7-tetrahydro-benzothiophene) mouse model CCl4-induced injury. C57BL/6 mice received weekly injections...

Early alpha interferon (IFN-alpha) therapy against hepatitis C virus (HCV) rescues polyfunctional, virus-specific memory CD8(+) T cells, but whether immune restoration is possible during late remains controversial. We compared of HCV-specific cells in patients who cleared HCV infection spontaneously and following early or IFN therapy. Multifunctional CD4(+) were detected spontaneous resolvers individuals treated an acute infection. In contrast, limited responses chronic infection, the...

The ubiquitin system plays a critical role in muscle wasting. Previous work has focused on the roles of ubiquitination. However, for deubiquitination this process not been established. Because ubiquitin-specific protease (USP)19 deubiquitinating enzyme is induced skeletal many catabolic conditions, we generated USP19 knockout (KO) mice. These mice lost less mass than wild-type (WT) animals response to glucocorticoids, common systemic cause atrophy as well denervation, model disuse atrophy....

Most individuals exposed to hepatitis C virus (HCV) become persistently infected while a minority spontaneously eliminate the virus. Although early immune events influence infection outcome, cellular composition, molecular effectors, and timeframe of host response active shortly after viral exposure remain incompletely understood. Employing specimens collected from people who inject drugs (PWID) with high risk HCV exposure, we utilized RNA-Seq blood transcriptome module (BTM) analysis...

AbstractUbiquitin-specific processing proteases (UBPs) presently form the largest enzyme family in ubiquitin system, characterized by a core region containing conserved motifs surrounded divergent sequences, most commonly at N-terminal end. The functions of these sequences remain unclear. We identified two isoforms novel testis-specific UBP, UBP-t1 and UBP-t2, which contain identical regions but distinct N termini, thereby permitting dissection regions. Both were germ cell specific...

Abstract Although it is well known that catecholamines inhibit skeletal muscle protein degradation, the molecular underlying mechanism remains unclear. This study was undertaken to investigate role of β2-adrenoceptors (AR) and cAMP in regulating ubiquitin-proteasome system (UPS) muscle. We report increased levels isolated muscles, promoted by phosphodiesterase inhibitor isobutylmethylxanthine accompanied decreased activity UPS, ubiquitin-protein conjugates, expression atrogin-1, a key ligase...

Summary Endogenous 24-hour rhythms are generated by circadian clocks located in most tissues. The molecular clock mechanism is based on feedback loops involving genes and their protein products. Post-translational modifications, including ubiquitination, important for regulating the mechanism. Previous work has focused role of ubiquitin ligases Here we show a rhythmically-expressed deubiquitinating enzyme specific peptidase 2 (USP2) function. Mice with deletion Usp2 gene (Usp2 KO) display...

Upon fasting, the ubiquitin-dependent proteolytic system is activated in skeletal muscle parallel with increases rates of proteolysis. Levels mRNA encoding 14 kDa ubiquitin-conjugating enzyme (E214k), which can catalyse first irreversible reaction this pathway, rise and fall proteolysis [Wing Banville (1994) Am. J. Physiol. 267, E39-E48], indicating that conjugation ubiquitin to proteins a regulated step. To characterize mechanisms regulation, we have examined effects insulin, insulin-like...

The Saccharomyces cerevisiae ubiquitin-conjugating enzymes (E2s) UBC4 and UBC5 are essential for degradation of short-lived abnormal proteins. We previously identified rat cDNAs encoding two E2s with strong sequence similarity to UBC5. These E2 isoforms widely expressed in tissues, consistent a fundamental cellular function these E2s. now report new isoform, 8A, which despite having >91% amino acid identity the other isoforms, shows several novel features. Expression 8A isoform appears...

We previously reported that the USP19 deubiquitinating enzyme positively regulates proliferation in fibroblasts by stabilizing KPC1, a ubiquitin ligase for p27(Kip1). To explore whether this role of extends to other cellular systems, we tested effects silencing several human prostate and breast models, including carcinoma cell lines. Depletion inhibited cancer DU145, PC-3 22RV1 cells, which was similar pattern established it due decreased progression from G1 S phase associated with...

Early appearance of neutralizing antibodies during acute hepatitis C virus (HCV) infection is associated with spontaneous viral clearance. However, the longitudinal changes in antigen-specific memory B cell (MBCs) divergent HCV outcomes remain undefined. We characterized E2 glycoprotein-specific MBCs from subjects who either spontaneously resolved or progressed to chronic infection, using single-cell RNA-seq and functional assays. HCV-specific plasma chronically infected recognized multiple...

The activity of the ubiquitin-dependent proteolytic system in differentiated tissues under basal conditions remains poorly explored. We measured rates ubiquitination rat tissue extracts. Accumulation ubiquitinated proteins increased presence ubiquitin aldehyde, indicating that deubiquitinating enzymes can regulate ubiquitination. Rates varied fourfold, with highest rate testis. tested whether ubiquitin-activating enzyme (E1) or ubiquitin-conjugating (E2s) could be limiting for conjugation....