DUSP6
Dual specificity protein phosphatase 6 (EC 3.1.3.16) (EC 3.1.3.48) (Dual specificity protein phosphatase PYST1) (Mitogen-activated protein kinase phosphatase 3) (MAP kinase phosphatase 3) (MKP-3) [MKP3] [PYST1]
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T cell dysfunction has a crucial role in establishing and maintaining viral persistence. We have previously shown a decline in miR-181a, which regulates CD4 T cell responses via DUSP6 overexpression, in individuals with hepatitis C virus (HCV) infection. Here, we describe accelerated T cell senescence in HCV-infected individuals compared with age- and sex-matched healthy subjects. Mechanistic studies revealed that up-regulation of transcription factor ΔNp63 led to the decline of miR-181a expression, resulting in an overexpression of the antiaging protein Sirt1, in CD4 T cells from HCV-infected individuals. Either reconstituting miR-181a or silencing ΔNp63 or Sirt1 expression in CD4 T cells led to accelerated T cell senescence, as evidenced by an increased senescence-associated β-galactosidase (SA-β-gal) expression, shortened telomere length, and decreased EdU incorporation; this suggests that HCV-induced T cell senescence is counterregulated by the ΔNp63-miR-181a-Sirt1 pathway. An increase of IL-2 production was observed in these senescent CD4 T cells and was driven by a markedly reduced frequency of Foxp3 regulatory T (T ) cells and increased number of Foxp3 effector T (T ) cells upon manipulating the ΔNp63-miR-181a-Sirt1 pathway. In conclusion, these findings provide novel mechanistic insights into how HCV uses cellular senescent pathways to regulate T cell functions, revealing new targets for rejuvenating impaired T cell responses during chronic viral infection.
MeSH Terms
- Adult
- Aged
- CD4-Positive T-Lymphocytes
- Case-Control Studies
- Cellular Senescence
- Female
- Genes, Reporter
- Hepatitis C, Chronic
- Humans
- Interleukin-2
- Male
- MicroRNAs
- Middle Aged
- Signal Transduction
- Sirtuin 1
- Telomere Shortening
- Transcription Factors
- Transfection
- Tumor Suppressor Proteins
- Up-Regulation
Keywords
- T cell senescence
- Sirtuin 1
- hepatitis C
- microRNA-181a
- transcription factor p63
The ability of the human immune system to respond to vaccination declines with age. We identified an age-associated defect in T cell receptor (TCR)-induced extracellular signal-regulated kinase (ERK) phosphorylation in naive CD4( ) T cells, whereas other signals, such as ζ chain-associated protein kinase 70 (ZAP70) and phospholipase C-γ1 phosphorylation, were not impaired. The defective ERK signaling was caused by the dual specific phosphatase 6 (DUSP6), whose protein expression increased with age due to a decline in repression by miR-181a. Reconstitution of miR-181a lowered DUSP6 expression in naive CD4( ) T cells in elderly individuals. DUSP6 repression using miR-181a or specific siRNA and DUSP6 inhibition by the allosteric inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one improved CD4( ) T cell responses, as seen by increased expression of activation markers, improved proliferation and supported preferential T helper type 1 cell differentiation. DUSP6 is a potential intervention target for restoring T cell responses in the elderly, which may augment the effectiveness of vaccination.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD4-Positive T-Lymphocytes
- Cell Differentiation
- Cell Proliferation
- Cells, Cultured
- Cyclohexylamines
- Dual Specificity Phosphatase 6
- Extracellular Signal-Regulated MAP Kinases
- Female
- Humans
- Indenes
- Lymphocyte Activation
- MAP Kinase Signaling System
- Male
- MicroRNAs
- Middle Aged
- Phosphorylation
- Receptors, Antigen, T-Cell
- ZAP-70 Protein-Tyrosine Kinase
Twin studies have shown that longevity in humans is moderately heritable with a genetic component of 25-32%. Experimental model organisms point to the existence of core survival and anti-ageing pathways that have been conserved throughout evolution. It has been shown that mutations in single genes involved in these pathways can either delay or accelerate the ageing process and that many of these genes and pathways are also present in humans. Here, we performed a targeted investigation of selected genes (i) involved in longevity pathways (insulin receptor/insulin-like growth factor-I signaling and energy metabolism, intracellular signaling, apoptosis and stress response) and (ii) in which mutations lead to genetic perturbations in animal models or human diseases. Altogether, we tested 500 nonsynonymous single nucleotide polymorphisms (SNPs) in 343 candidate genes for association with the longevity phenotype in a German sample comprising about 400 centenarians and an equal number of younger control subjects. Thus, this study presents one of the largest candidate studies in human genetic longevity research conducted to-date. The three top-ranking markers, which are located in the genes DUSP6, NALP1 and PERP, revealed p-values≤0.01 in the allelic case-control comparisons. Although the association signals in Germans were not replicated in an independent French sample, the large number of analysis results is deemed a valuable reference point for further genetic studies.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Alleles
- Case-Control Studies
- Female
- Genetic Predisposition to Disease
- Humans
- Longevity
- Male
- Middle Aged
- Models, Genetic
- Polymorphism, Single Nucleotide
- Tumor Suppressor Protein p53
A fully developed, functional epididymis is important for male fertility. In particular, it is apparent that without the most proximal region, the initial segment (IS), infertility results. Therefore, it is important to understand the development and regulation of this crucial epididymal region. We have previously shown that many functions of the IS are regulated by luminal fluid factors/lumicrine factors from the testis. This study provides evidence that lumicrine factors activated the ERK pathway only in epithelial cells of the IS from Postnatal Day (P) 14 to P19 and sustained this activation into adulthood. The activated ERK pathway promoted cell proliferation and differentiation in the developing IS, although in the adult, its role was switched to maintain cell survival. To understand further the regulation of cell proliferation in the IS, we examined the role of DUSP6, an MAPK1/3 (ERK1/2) preferred phosphatase that is also regulated by lumicrine factors in the IS. Utilizing Dusp6(-/-) mice, our studies, surprisingly, revealed that Dusp6 was a major regulator of cell proliferation in the caput and corpus regions, whereas components of the ERK pathway, together with PTEN and SRC, were the major regulators of cell proliferation in the IS. We hypothesize that region-specific regulation of cell proliferation is caused by differences in the balance of activities between pro- and antiproliferation signaling pathway components for each epididymal region. An understanding of the mechanisms of cell proliferation may provide clues as to why the epididymis rarely succumbs to cancer.
MeSH Terms
- Aging
- Animals
- Cell Proliferation
- Cell Survival
- Dual Specificity Phosphatase 6
- Epididymis
- Gene Expression Regulation, Developmental
- Genes, src
- Ligation
- MAP Kinase Signaling System
- Male
- Mice
- Mice, Knockout
- Mitogen-Activated Protein Kinase 1
- Mitogen-Activated Protein Kinase 3
- Organ Specificity
- PTEN Phosphohydrolase
- Phosphorylation
- Protein Array Analysis
- RNA, Messenger
- Testicular Hormones