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Norikazu Kiguchi, Huiping Ding, Christopher M Peters, Nancy D Kock, Shiroh Kishioka, J Mark Cline, Janice D Wagner, Mei-Chuan Ko
Neuroinflammation is a pathological condition that underlies diabetes and affects sensory processing. Given the high prevalence of pain in diabetic patients and crosstalk between chemokines and opioids, it is pivotal to know whether neuroinflammation-associated mediators are dysregulated in the central nervous system of diabetic primates. Therefore, the aim of this study was to investigate whether mRNA expression levels of glial markers, chemokines, and opioid receptors are altered in the spinal cord and thalamus of naturally occurring type 2 diabetic monkeys (n=7) compared with age-matched non-diabetic monkeys (n=6)...
October 14, 2016: Biochimica et Biophysica Acta
Xiaofeng Zheng, Pengyi Yang, Brad Lackford, Brian D Bennett, Li Wang, Hui Li, Yu Wang, Yiliang Miao, Julie F Foley, David C Fargo, Ying Jin, Carmen J Williams, Raja Jothi, Guang Hu
Poly(A) tail length and mRNA deadenylation play important roles in gene regulation. However, how they regulate embryonic development and pluripotent cell fate is not fully understood. Here we present evidence that CNOT3-dependent mRNA deadenylation governs the pluripotent state. We show that CNOT3, a component of the Ccr4-Not deadenylase complex, is required for mouse epiblast maintenance. It is highly expressed in blastocysts and its deletion leads to peri-implantation lethality. The epiblast cells in Cnot3 deletion embryos are quickly lost during diapause and fail to outgrow in culture...
October 8, 2016: Stem Cell Reports
Matthew N Davies, Helene Pere, Iris Bosschem, Freddy Haesebrouck, Bram Flahou, Eric Tartour, Darren R Flower, David F Tough, Jagadeesh Bayry
Adjuvants are substances that boost the protective immune response to vaccine antigens. The majority of known adjuvants have been identified through the use of empirical approaches. Our aim was to identify novel adjuvants with well-defined cellular and molecular mechanisms by combining a knowledge of immunoregulatory mechanisms with an in silico approach. CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) inhibit the protective immune responses to vaccines by suppressing the activation of antigen presenting cells such as dendritic cells (DCs)...
2017: Methods in Molecular Biology
Wei-Lun Chou, Yue-Lin Chung, Jhen-Cheng Fang, Chung-An Lu
Rice is an important crop in the world. However, little is known about rice mRNA deadenylation, which is an important regulation step of gene expression at the post-transcriptional level. The CCR4-NOT1 complex contains two key components, CCR4 and CAF1, which are the main cytoplasmic deadenylases in eukaryotic cells. In yeast and humans, CCR4 can interact with CAF1 via its N-terminal LRR domain. However, no CCR4 protein containing N-terminal LRR motifs have been found in plants. In this manuscript, we demonstrate a novel pattern of interaction between OsCCR4 and OsCAF1 in the rice CCR4-NOT complex, and that OsCAF1 acts as a bridge between OsCCR4 and OsNOT1 in this complex...
October 6, 2016: Plant Molecular Biology
Felicitas Rataj, Séverine Planel, Agnès Desroches-Castan, Juliette Le Douce, Khadija Lamribet, Josiane Denis, Jean-Jacques Feige, Nadia Cherradi
TIS11b/BRF1 belongs to the Tristetraprolin (TTP) family of zinc-finger proteins which bind to mRNAs containing AU-rich elements (ARE) in their 3'-untranslated region and target them for degradation. Regulation of TTP family function through phosphorylation by p38 MAPK and PKB/Akt signalling pathways has been extensively studied. In contrast, the role of cAMP-dependent protein kinase (PKA) in the control of TTP family activity in mRNA decay remains largely unknown. Here, we show that PKA activation induces TIS11b gene expression and protein phosphorylation...
October 5, 2016: Molecular Biology of the Cell
Xia Li, Tetsuro Ohmori, Kaoru Irie, Yuichi Kimura, Yasuyuki Suda, Tomoaki Mizuno, Kenji Irie
Ccr4, a component of the Ccr4-Not cytoplasmic deadenylase complex, is known to be required for the cell wall integrity (CWI) pathway in the budding yeast Saccharomyces cerevisiae. However, it is not fully understood how Ccr4 and other components of the Ccr4-Not complex regulate the CWI pathway. Previously, we showed that Ccr4 functions in the CWI pathway together with Khd1 RNA binding protein. Ccr4 and Khd1 modulate a signal from Rho1 small GTPase in the CWI pathway by regulating the expression of ROM2 mRNA and LRG1 mRNA, encoding a guanine nucleotide exchange factor (GEF) and a GTPase-activating protein (GAP) for Rho1, respectively...
September 2016: MSphere
Edlyn Wu, Ajay A Vashisht, Clément Chapat, Mathieu N Flamand, Emiliano Cohen, Mihail Sarov, Yuval Tabach, Nahum Sonenberg, James Wohlschlegel, Thomas F Duchaine
MicroRNAs (miRNAs) impinge on the translation and stability of their target mRNAs, and play key roles in development, homeostasis and disease. The gene regulation mechanisms they instigate are largely mediated through the CCR4-NOT deadenylase complex, but the molecular events that occur on target mRNAs are poorly resolved. We observed a broad convergence of interactions of germ granule and P body mRNP components on AIN-1/GW182 and NTL-1/CNOT1 in Caenorhabditis elegans embryos. We show that the miRISC progressively matures on the target mRNA from a scanning form into an effector mRNP particle by sequentially recruiting the CCR4-NOT complex, decapping and decay, or germ granule proteins...
October 3, 2016: Nucleic Acids Research
Yi Dai, Zhongye Cao, Lihong Huang, Shixia Liu, Zhihui Shen, Yuyan Wang, Hui Wang, Huijuan Zhang, Dayong Li, Fengming Song
CCR4-Not complex is a multifunctional regulator that plays important roles in multiple cellular processes in eukaryotes. In the present study, the biological function of FonNot2, a core subunit of the CCR4-Not complex, was explored in Fusarium oxysporum f. sp. niveum (Fon), the causal agent of watermelon wilt disease. FonNot2 was expressed at higher levels in conidia and germinating conidia and during infection in Fon-inoculated watermelon roots than in mycelia. Targeted disruption of FonNot2 resulted in retarded vegetative growth, reduced conidia production, abnormal conidial morphology, and reduced virulence on watermelon...
2016: Frontiers in Microbiology
Christopher Frederick Mugler, Maria Hondele, Stephanie Heinrich, Ruchika Sachdev, Pascal Vallotton, Adriana Y Koek, Leon Y Chan, Karsten Weis
Translational repression and mRNA degradation are critical mechanisms of posttranscriptional gene regulation that help cells respond to internal and external cues. In response to certain stress conditions, many mRNA decay factors are enriched in processing bodies (PBs), cellular structures involved in degradation and/or storage of mRNAs. Yet, how cells regulate assembly and disassembly of PBs remains poorly understood. Here, we show that in budding yeast, mutations in the DEAD-box ATPase Dhh1 that prevent ATP hydrolysis, or that affect the interaction between Dhh1 and Not1, the central scaffold of the Ccr4-NOT complex and an activator of the Dhh1 ATPase, prevent PB disassembly in vivo...
October 3, 2016: ELife
Guilherme de Paula Costa, Laís Roquete Lopes, Maria Cláudia da Silva, Aline Luciano Horta, Washington Martins Pontes, Cristiane M Milanezi, Paulo Marcos da Mata Guedes, Wanderson Geraldo de Lima, Richard Schulz, João Santana da Silva, Andre Talvani
Chemokines (CKs) and chemokine receptors (CKR) promote leukocyte recruitment into cardiac tissue infected by the Trypanosoma cruzi. This study investigated the long-term treatment with subantimicrobial doses of doxycycline (Dox) in association, or not, with benznidazole (Bz) on the expression of CK and CKR in cardiac tissue. Thirty mongrel dogs were infected, or not, with the Berenice-78 strain of T. cruzi and grouped according their treatments: (i) two months after infection, Dox (50 mg/kg) 2x/day for 12 months; (ii) nine months after infection, Bz (3,5 mg/kg) 2x/day for 60 days; (iii) Dox + Bz; and (iv) vehicle...
2016: Mediators of Inflammation
Shelley Gorman, Sian Geldenhuys, Melinda Judge, Clare E Weeden, Jason Waithman, Prue H Hart
Skin inflammatory responses in individuals with allergic dermatitis may be suppressed by dietary vitamin D through induction and upregulation of the suppressive activity of regulatory T (TReg) cells. Vitamin D may also promote TReg cell tropism to dermal sites. In the current study, we examined the capacity of dietary vitamin D3 to modulate skin inflammation and the numbers and activity of TReg cells in skin and other sites including lungs, spleen, and blood. In female BALB/c mice, dietary vitamin D3 suppressed the effector phase of a biphasic ear swelling response induced by dinitrofluorobenzene in comparison vitamin D3-deficient female BALB/c mice...
2016: Journal of Immunology Research
Sahil Sharma, Fabian Poetz, Marius Bruer, Thi Bach Nga Ly-Hartig, Johanna Schott, Bertrand Séraphin, Georg Stoecklin
Acetylation of histones and transcription-related factors is known to exert epigenetic and transcriptional control of gene expression. Here we report that histone acetyltransferases (HATs) and histone deacetylases (HDACs) also regulate gene expression at the posttranscriptional level by controlling poly(A) RNA stability. Inhibition of HDAC1 and HDAC2 induces massive and widespread degradation of normally stable poly(A) RNA in mammalian and Drosophila cells. Acetylation-induced RNA decay depends on the HATs p300 and CBP, which acetylate the exoribonuclease CAF1a, a catalytic subunit of the CCR4-CAF1-NOT deadenlyase complex and thereby contribute to accelerating poly(A) RNA degradation...
September 15, 2016: Molecular Cell
Jared Klarquist, Kristen Tobin, Peyman Farhangi Oskuei, Steven W Henning, Manuel F Fernandez, Emilia R Dellacecca, Flor C Navarro, Jonathan M Eby, Shilpak Chatterjee, Shikhar Mehrotra, Joseph I Clark, I Caroline Le Poole
T regulatory cells (Treg) avert autoimmunity but their increased levels in melanoma confer a poor prognosis. To explore the basis for Treg accumulation in melanoma, we evaluated chemokine expression in patients. A 5-fold increase was documented in the Treg chemoattractants CCL22 and CCL1 in melanoma-affected skin versus unaffected skin, as accompanied by infiltrating FoxP3+ T cells. In parallel, there was a ~2-fold enhancement in expression of CCR4 in circulating Treg but not T effector cells. We hypothesized that redirecting Treg away from tumors might suppress autoimmune side-effects caused by immune checkpoint therapeutics now used widely in the clinic...
September 12, 2016: Cancer Research
Graham Dominick, Jacqueline Bowman, Xinna Li, Richard A Miller, Gonzalo G Garcia
Studies of the mTOR pathway have prompted speculation that diminished mTOR complex-1 (mTORC1) function may be involved in controlling the aging process. Our previous studies have shown diminished mTORC1 activity in tissues of three long-lived mutant mice: Snell dwarf mice, growth hormone receptor gene disrupted mice (GHRKO), and in this article, mice deficient in the pregnancy-associated protein-A (PAPPA-KO). The ways in which lower mTOR signals slow aging and age-related diseases are, however, not well characterized...
September 13, 2016: Aging Cell
Marta Mauri, Marieluise Kirchner, Reuven Aharoni, Camilla Ciolli Mattioli, David van den Bruck, Nadya Gutkovitch, Vengamanaidu Modepalli, Matthias Selbach, Yehu Moran, Marina Chekulaeva
Our current knowledge about the mechanisms of miRNA silencing is restricted to few lineages such as vertebrates, arthropods, nematodes and land plants. miRNA-mediated silencing in bilaterian animals is dependent on the proteins of the GW182 family. Here, we dissect the function of GW182 protein in the cnidarian Nematostella, separated by 600 million years from other Metazoa. Using cultured human cells, we show that Nematostella GW182 recruits the CCR4-NOT deadenylation complexes via its tryptophan-containing motifs, thereby inhibiting translation and promoting mRNA decay...
September 6, 2016: Nucleic Acids Research
Hong-Yeoul Ryu, Nicole R Wilson, Sameet Mehta, Soo Seok Hwang, Mark Hochstrasser
Post-translational protein modification by the small ubiquitin-related modifier (SUMO) regulates numerous cellular pathways, including transcription, cell division, and genome maintenance. The SUMO protease Ulp2 modulates many of these SUMO-dependent processes in budding yeast. From whole-genome RNA sequencing (RNA-seq), we unexpectedly discovered that cells lacking Ulp2 display a twofold increase in transcript levels across two particular chromosomes: chromosome I (ChrI) and ChrXII. This is due to the two chromosomes being present at twice their normal copy number...
August 15, 2016: Genes & Development
Yukie Tsubokura, Atsushi Satake, Masaaki Hotta, Hideaki Yoshimura, Shinya Fujita, Yoshiko Azuma, Takahisa Nakanishi, Aya Nakaya, Tomoki Ito, Kazuyoshi Ishii, Shosaku Nomura
A humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, mogamulizumab (MOG), has been shown to be safe and effective in the treatment of relapsed/refractory adult T-cell leukemia/lymphoma (ATLL). MOG depletes ATLL cells as well as regulatory T cells (Tregs), as CCR4 is expressed on these cells as well. In this context, pretransplant treatment with MOG may induce severe graft-versus-host disease (GVHD) in allogeneic hematopoietic stem-cell transplantation (HSCT). However, the influence of MOG on allogeneic HSCT, including its induction of GVHD, is unclear...
August 29, 2016: International Journal of Hematology
Rene Geissler, Andrew Grimson
The 3' untranslated regions (3'UTRs) of mammalian mRNAs direct an extensive range of alternative post-transcriptional outcomes, including regulation of mRNA decay and translation, contributing significantly to overall gene regulation. However, our knowledge of the underlying sequences and mechanisms is incomplete. We identified a novel 3'UTR sequence motif in mammals that targets mRNAs for transcript degradation. The motif is found in hundreds of mRNAs and is enriched in transcripts encoding regulatory proteins, such as transcription and signaling factors...
August 26, 2016: RNA Biology
Hao Du, Ya Zhao, Jinqiu He, Yao Zhang, Hairui Xi, Mofang Liu, Jinbiao Ma, Ligang Wu
Methylation at the N6 position of adenosine (m(6)A) is the most abundant RNA modification within protein-coding and long noncoding RNAs in eukaryotes and is a reversible process with important biological functions. YT521-B homology domain family (YTHDF) proteins are the readers of m(6)A, the binding of which results in the alteration of the translation efficiency and stability of m(6)A-containing RNAs. However, the mechanism by which YTHDF proteins cause the degradation of m(6)A-containing RNAs is poorly understood...
2016: Nature Communications
Vanessa Sue Wacleche, Jean-Philippe Goulet, Annie Gosselin, Patricia Monteiro, Hugo Soudeyns, Rémi Fromentin, Mohammad-Ali Jenabian, Shant Vartanian, Steven G Deeks, Nicolas Chomont, Jean-Pierre Routy, Petronela Ancuta
BACKGROUND: Th17 cells are permissive to HIV-1 infection and their depletion from the gut of infected individuals leads to microbial translocation, a major cause for non-AIDS co-morbidities. Most recent evidence supports the contribution of long-lived Th17 cells to HIV persistence during antiretroviral therapy (ART). However, the identity of long-lived Th17 cells remains unknown. RESULTS: Here, we performed an in-depth transcriptional and functional characterization of four distinct Th17 subsets and investigated their contribution to HIV reservoir persistence during ART...
2016: Retrovirology
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