Foxp3 inhibits HDAC1 activity to modulate gene expression in human T cells

We have previously reported that HIV-1 preferentially infects Foxp3+ Treg cells in vitro and in vivo, and Foxp3 enhances the HIV-1 LTR expression through epigenetic mechanisms in T cells. We report here that histone deacetylase inhibitor (HDACi) failed to further enhance HIV gene expression in FoxP3+ T cells. We discovered that Foxp3 inhibited cellular HDAC activity in T cells, and mutations in the forkhead domain that ablate Foxp3 function also abolished its ability to inhibit HDAC. When co-expressed, Foxp3 specifically inhibited the deacetylase activity of HDAC1. We further showed that Foxp3 was associated with HDAC1, and mutations in the forkhead domain that ablate Foxp3 function in Treg cells also inhibited Foxp3 association with and inhibition of HDAC1. Finally, Foxp3 failed to enhance HIV-1 gene expression in human T cells expressing HDAC1-specific shRNA. We conclude that Foxp3 modulates gene expression in human T cells at least partly by inhibiting HDAC1 activity

Foxp3 inhibits HDAC1 activity to modulate gene expression in human T cells

We have previously reported that HIV-1 preferentially infects Foxp3+ Treg cells in vitro and in vivo, and Foxp3 enhances the HIV-1 LTR expression through epigenetic mechanisms in T cells. We report here that histone deacetylase inhibitor (HDACi) failed to further enhance HIV gene expression in FoxP3+ T cells. We discovered that Foxp3 inhibited cellular HDAC activity in T cells, and mutations in the forkhead domain that ablate Foxp3 function also abolished its ability to inhibit HDAC. When co-expressed, Foxp3 specifically inhibited the deacetylase activity of HDAC1. We further showed that Foxp3 was associated with HDAC1, and mutations in the forkhead domain that ablate Foxp3 function in Treg cells also inhibited Foxp3 association with and inhibition of HDAC1. Finally, Foxp3 failed to enhance HIV-1 gene expression in human T cells expressing HDAC1-specific shRNA. We conclude that Foxp3 modulates gene expression in human T cells at least partly by inhibiting HDAC1 activity

HIV-1 Infection Induces Interleukin-1β Production via TLR8 Protein-dependent and NLRP3 Inflammasome Mechanisms in Human Monocytes

The induction of inflammatory cytokines such as IL-1β is associated with the progression of human immunodeficiency virus, type 1 (HIV-1) disease or AIDS. Unlike most inflammatory cytokines that are regulated by NF-κB at the transcriptional level, production of mature IL-1β also depends on inflammasome activation. The mechanism by which HIV-1 induces pro-IL-1β expression and activates inflammasomes to cleave pro-IL-1β into its bioactive form is not clearly defined. We report here that HIV-1 infection in human monocytes efficiently induced IL-1β expression and inflammasome activation. Toll-like receptor 8 (TLR8) was required for inducing pro-IL-1β expression, whereas the NLRP3 inflammasome was required for IL-1β maturation and release. Furthermore, the lysosomal protease cathepsin B and HIV-1 induced production of reactive oxygen species were critical for HIV-induced inflammasome activation and IL-1β production. HIV-1 entry, reverse transcription, and integration were all required for both pro-IL-1β expression and inflammasome activation. Finally, we show that HIV-1-derived RNA was sufficient to induce both pro-IL-1β expression and inflammasome activation. We conclude that HIV-1 infection induced the expression of pro-IL-1β via TLR8-mediated mechanisms and activated caspase-1 through the NLRP3 inflammasome to cleave pro-IL-1β into bioactive IL-1β. These findings help to elucidate mechanisms of HIV-1 disease progression and identify novel targets for treating HIV-1 induced inflammation and immune activation

RING finger 138 deregulation distorts NF-кB signaling and facilities colitis switch to aggressive malignancy

Prolonged activation of nuclear factor (NF)-кB signaling significantly contributes to the development of colorectal cancer (CRC). New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction. Here, we discovered the critical role of RING finger 138 (RNF138) in CRC tumorigenesis through regulating the NF-кB signaling, which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response. RNF138(−/−) mice were hyper-susceptible to the switch from colitis to aggressive malignancy, which coincided with sustained aberrant NF-кB signaling in the colonic cells. Furthermore, RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein (NIBP) to the cytoplasm, which requires the ubiquitin interaction motif (UIM) domain. More importantly, we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings, raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling. Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients, we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth. Overall, our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression, and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation

Research Trends and Hotspots Analysis Related to Monocarboxylate Transporter 1: A Study Based on Bibliometric Analysis

Background: Monocarboxylate transport protein 1 (MCT1) has been defined as a critical regulator in tumor energy metabolism, but bibliometric analysis of MCT1 research is rare. This study aimed to comprehensively analyze the global scientific output of MCT1 research and explore the hotspots and frontiers from the past decade. Methods: Publications and their literature information from 2008 to 2018 were retrieved from the Web of Science Core Collection database. We used Microsoft Excel 2016 to detect the trend of annual numbers of publications, and used Citespace V software as the bibliometric method to analyze the research areas, countries, institutions, authors, journals, research hotspots, and research frontiers. Results: A total of 851 publications were identified with an increasing trend. Relevant literature mainly focused on the field of oncology. The most prolific country and institution were the USA and University of Minho, respectively. Baltazar was the most productive author while Halestrap had the highest co-citations. The hottest topics in MCT1 were hypoxia, gene expression, and CD147 over the last decade. The three research frontier topics were proliferation, tumor cell, and resistance. The special role of MCT1 in human tumor cells has become the focus for scholars recently. Conclusion: The development prospects of MCT1 research could be expected and researchers should pay attention to the clinical significance of MCT1 inhibitors as anti-cancer or immunosuppressive drugs and the possibility of drug-resistance formation

Synthesis, structure and dehydrogenation of zirconium borohydride octaammoniate

A new metal borohydride ammoniate (MBA), Zr(BH4)4·8NH3, was synthesized via ammoniation of the Zr(BH4)4 crystal. Zr(BH4)4·8NH3 has a distinctive structure and the highest coordination number of NH3 groups among all the known MBAs. This compound could quickly dehydrogenate at 130 °C, enabling it a potential hydrogen storage material

Structural basis for the immunomodulatory function of cysteine protease inhibitor from human roundworm Ascaris lumbricoides.

Immunosuppression associated with infections of nematode parasites has been documented. Cysteine protease inhibitor (CPI) released by the nematode parasites is identified as one of the major modulators of host immune response. In this report, we demonstrated that the recombinant CPI protein of Ascaris lumbricoides (Al-CPI) strongly inhibited the activities of cathepsin L, C, S, and showed weaker effect to cathepsin B. Crystal structure of Al-CPI was determined to 2.1 Å resolution. Two segments of Al-CPI, loop 1 and loop 2, were proposed as the key structure motifs responsible for Al-CPI binding with proteases and its inhibitory activity. Mutations at loop 1 and loop 2 abrogated the protease inhibition activity to various extents. These results provide the molecular insight into the interaction between the nematode parasite and its host and will facilitate the development of anthelmintic agents or design of anti-autoimmune disease drugs

Characterization and virulence of Streptococcus agalactiae deficient in EIIA of the cellobiose-specific phosphotransferase system

To indicate the EIIA protein of cellobiose-specific phosphotransferase transport system in affecting the characterization and virulence of Streptococcus agalactiae. A △cel-EIIA mutant was constructed from the wild-type S. agalactiae THN0901 strain by homologous recombination. In the present study, the cellobiose metabolism and biofilm formation of the △cel-EIIA mutant was significantly decreased, relative to that of the wild-type S. agalactiae THN0901. The proliferation capacity in vitro and the invasion and colonization ability in vivo of the △cel-EIIA mutant was also significantly lower than that of S. agalactiae THN0901. Furthermore, in tilapia infection model, the lethal dose 50 % the △cel-EIIA mutant was significantly higher than that of the wild strain. Taken together, the cel-EIIA gene plays a positive role in S. agalactiae cellobiose metabolism, biofilm formation and colonization of tilapia. The results of this study provide the basic data for the cellobiose metabolism and virulence mechanism in S. agalactiae of tilapia in the future

Overcoming biomass recalcitrance by synergistic pretreatment of mechanical activation and metal salt for enhancing enzymatic conversion of lignocellulose

Abstract Background Due to biomass recalcitrance, including complexity of lignocellulosic matrix, crystallinity of cellulose, and inhibition of lignin, the bioconversion of lignocellulosic biomass is difficult and inefficient. The aim of this study is to investigate an effective and green pretreatment method for overcoming biomass recalcitrance of lignocellulose. Results An effective mechanical activation (MA) + metal salt (MAMS) technology was applied to pretreat sugarcane bagasse (SCB), a typical kind of lignocellulosic biomass, in a stirring ball mill. Chlorides and nitrates of Al and Fe showed better synergistic effect with MA, especially AlCl3, ascribing to the interaction between metal salt and oxygen-containing groups induced by MA. Comparative studies showed that MAMS pretreatment effectively changed the recalcitrant structural characteristics of lignocellulosic matrix and reduced the inhibitory action of lignin on enzymatic conversion of SCB. The increase in hydroxyl and carboxyl groups of lignin induced by MAMS pretreatment led to the increase of its hydrophilicity, which could weaken the binding force between cellulase and lignin and reduce the nonproductive binding of cellulase enzymes to lignin. Conclusions MAMS pretreatment significantly enhanced the enzymatic digestibility of polysaccharides substrate by overcoming biomass recalcitrance without the removal of lignin from enzymatic hydrolysis system