Concise review: The heterogenous roles of BATF3 in cancer oncogenesis and dendritic cells and T cells differentiation and function considering the importance of BATF3-dependent dendritic cells.

The transcription factor, known as basic leucine zipper ATF-like 3 (BATF3), is a crucial contributor to the development of conventional type 1 dendritic cells (cDC1), which is definitely required for priming CD8 + T cell-mediated immunity against intracellular pathogens and malignancies. In this respect, BATF3-dependent cDC1 can bring about immunological tolerance, an autoimmune response, graft immunity, and defense against infectious agents such as viruses, microbes, parasites, and fungi. Moreover, the important function of cDC1 in stimulating CD8 + T cells creates an excellent opportunity to develop a highly effective target for vaccination against intracellular pathogens and diseases. BATF3 has been clarified to control the development of CD8α+ and CD103+ DCs. The presence of BATF3-dependent cDC1 in the tumor microenvironment (TME) reinforces immunosurveillance and improves immunotherapy approaches, which can be beneficial for cancer immunotherapy. Additionally, BATF3 acts as a transcriptional inhibitor of Treg development by decreasing the expression of the transcription factor FOXP3. However, when overexpressed in CD8 + T cells, it can enhance their survival and facilitate their transition to a memory state. BATF3 induces Th9 cell differentiation by binding to the IL-9 promoter through a BATF3/IRF4 complex. One of the latest research findings is the oncogenic function of BATF3, which has been approved and illustrated in several biological processes of proliferation and invasion.

The basic leucine zipper transcription factor OsbZIP83 and the glutaredoxins OsGRX6 and OsGRX9 facilitate rice iron utilization under the control of OsHRZ ubiquitin ligases.

Under low iron availability, plants induce the expression of various genes for iron uptake and translocation. The rice (Oryza sativa) ubiquitin ligases OsHRZ1 and OsHRZ2 cause overall repression of these iron-related genes at the transcript level, but their protein-level regulation is unclear. We conducted a proteome analysis to identify key regulators whose abundance was regulated by OsHRZs at the protein level. In response to iron deficiency or OsHRZ knockdown, many genes showed differential regulation between the transcript and protein levels, including the TGA-type basic leucine zipper transcription factor OsbZIP83. We also identified two glutaredoxins, OsGRX6 and OsGRX9, as OsHRZ-interacting proteins in yeast and plant cells. OsGRX6 also interacted with OsbZIP83. Our in vitro degradation assay suggested that OsbZIP83, OsGRX6 and OsGRX9 proteins are subjected to 26S proteasome- and OsHRZ-dependent degradation. Proteome analysis and our in vitro degradation assay also suggested that OsbZIP83 protein was preferentially degraded under iron-deficient conditions in rice roots. Transgenic rice lines overexpressing OsGRX9 and OsbZIP83 showed improved tolerance to iron deficiency. Expression of iron-related genes was affected in the OsGRX9 and OsGRX6 knockdown lines, suggesting disturbed iron utilization and signaling. OsbZIP83 overexpression lines showed enhanced expression of OsYSL2 and OsNAS3, which are involved in internal iron translocation, in addition to OsGRX9 and genes related to phytoalexin biosynthesis and the salicylic acid pathway. The results suggest that OsbZIP83, OsGRX6 and OsGRX9 facilitate iron utilization downstream of the OsHRZ pathway.

IRF8 and BATF3 interaction enhances the cDC1 specific Pfkfb3 gene expression.

Dendritic cells (DCs) play central role in innate as well as adaptive immune responses regulated by diverse DC subtypes that vary in terms of surface markers, transcriptional profile and functional responses. Generation of DC diversity from progenitor stage is tightly regulated by complex molecular inter-play between transcription factors. We earlier demonstrated that Batf3 and Id2 expression have a synergistic effect on the Irf8 directed classical cDC1 development. In present study, Bi-molecular fluorescence complementation assay suggested that IRF8 interacts with BATF3, and ID2 may aid cDC1 development independently. Genome wide recruitment analysis of IRF8 and BATF3 from different DC subtypes led to identification of the overlapping regions of occupancy by these two transcription factors. Further analysis of overlapping peaks of IRF8 and BATF3 occupancy in promoter region within the cDC1 subtype specific transcriptional pattern identified a metabolically important Pfkfb3 gene. Among various immune cell types; splenic cDC1 subtype displayed enhanced expression of Pfkfb3. Analysis of Irf8-/-, Irf8R294C and Batf3DCKO DC confirmed direct regulation of Pfkfb3 enhanced expression specifically in cDC1 subtype. Further we show that inhibition of PFKFB3 enzymatic activity by a chemical agent PFK15 led to reduction in cDC1 subtype in both in vitro FLDC cultures as well as in vivo mouse spleens. Together, our study identified the direct regulation of cDC1 specific enhanced expression of Pfkfb3 in glycolysis and cDC1 biology.

OsbZIP18, a Positive Regulator of Serotonin Biosynthesis, Negatively Controls the UV-B Tolerance in Rice.

Serotonin (5-hydroxytryptamine) plays an important role in many developmental processes and biotic/abiotic stress responses in plants. Although serotonin biosynthetic pathways in plants have been uncovered, knowledge of the mechanisms of serotonin accumulation is still limited, and no regulators have been identified to date. Here, we identified the basic leucine zipper transcription factor OsbZIP18 as a positive regulator of serotonin biosynthesis in rice. Overexpression of OsbZIP18 strongly induced the levels of serotonin and its early precursors (tryptophan and tryptamine), resulting in stunted growth and dark-brown phenotypes. A function analysis showed that OsbZIP18 activated serotonin biosynthesis genes (including tryptophan decarboxylase 1 (OsTDC1), tryptophan decarboxylase 3 (OsTDC3), and tryptamine 5-hydroxylase (OsT5H)) by directly binding to the ACE-containing or G-box cis-elements in their promoters. Furthermore, we demonstrated that OsbZIP18 is induced by UV-B stress, and experiments using UV-B radiation showed that transgenic plants overexpressing OsbZIP18 exhibited UV-B stress-sensitive phenotypes. Besides, exogenous serotonin significantly exacerbates UV-B stress of OsbZIP18_OE plants, suggesting that the excessive accumulation of serotonin may be responsible for the sensitivity of OsbZIP18_OE plants to UV-B stress. Overall, we identified a positive regulator of serotonin biosynthesis and demonstrated that UV-B-stress induced serotonin accumulation, partly in an OsbZIP18-dependent manner.

Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBPß.

Skeletal muscle atrophy is a highly-prevalent and debilitating condition that remains poorly understood at the molecular level. Previous work found that aging, fasting, and immobilization promote skeletal muscle atrophy via expression of activating transcription factor 4 (ATF4) in skeletal muscle fibers. However, the direct biochemical mechanism by which ATF4 promotes muscle atrophy is unknown. ATF4 is a member of the basic leucine zipper transcription factor (bZIP) superfamily. Because bZIP transcription factors are obligate dimers, and because ATF4 is unable to form highly-stable homodimers, we hypothesized that ATF4 may promote muscle atrophy by forming a heterodimer with another bZIP family member. To test this hypothesis, we biochemically isolated skeletal muscle proteins that associate with the dimerization- and DNA-binding domain of ATF4 (the bZIP domain) in mouse skeletal muscle fibers in vivo Interestingly, we found that ATF4 forms at least five distinct heterodimeric bZIP transcription factors in skeletal muscle fibers. Furthermore, one of these heterodimers, composed of ATF4 and CCAAT enhancer-binding protein ß (C/EBPß), mediates muscle atrophy. Within skeletal muscle fibers, the ATF4-C/EBPß heterodimer interacts with a previously unrecognized and evolutionarily conserved ATF-C/EBP composite site in exon 4 of the Gadd45a gene. This three-way interaction between ATF4, C/EBPß, and the ATF-C/EBP composite site activates the Gadd45a gene, which encodes a critical mediator of muscle atrophy. Together, these results identify a biochemical mechanism by which ATF4 induces skeletal muscle atrophy, providing molecular-level insights into the etiology of skeletal muscle atrophy.

Arabidopsis CPK6 positively regulates ABA signaling and drought tolerance through phosphorylating ABA-responsive element-binding factors.

Abscisic acid (ABA) regulates numerous developmental processes and drought tolerance in plants. Calcium-dependent protein kinases (CPKs) are important Ca2+ sensors playing crucial roles in plant growth and development as well as responses to stresses. However, the molecular mechanisms of many CPKs in ABA signaling and drought tolerance remain largely unknown. Here we combined protein interaction studies, and biochemical and genetic approaches to identify and characterize substrates that were phosphorylated by CPK6 and elucidated the mechanism that underlines the role of CPK6 in ABA signaling and drought tolerance. The expression of CPK6 is induced by ABA and dehydration. Two cpk6 T-DNA insertion mutants are insensitive to ABA during seed germination and root elongation of seedlings; in contrast, overexpression of CPK6 showed the opposite phenotype. Moreover, CPK6-overexpressing lines showed enhanced drought tolerance. CPK6 interacts with and phosphorylates a subset of core ABA signaling-related transcription factors, ABA-responsive element-binding factors (ABFs/AREBs), and enhances their transcriptional activities. The phosphorylation sites in ABF3 and ABI5 were also identified through MS and mutational analyses. Taken together, we present evidence that CPK6 mediates ABA signaling and drought tolerance through phosphorylating ABFs/AREBs. This work thus uncovers a rather conserved mechanism of calcium-dependent Ser/Thr kinases in ABA signaling.

OsbZIP42 is a positive regulator of ABA signaling and confers drought tolerance to rice.

MAIN CONCLUSION: OsbZIP42 is a positive regulator of ABA signaling and drought stress tolerance. The activation of OsbZIP42 depends on stress-/ABA-activated protein kinase 4 (SAPK4) and an additional ABA-dependent modification of OsbZIP42. Basic leucine zipper transcription factors (bZIP TFs) play important roles in the ABA signaling pathway in plants. Rice OsbZIP42 is a member of the group E bZIP, which is an ortholog of Arabidopsis group A bZIP. This latter group includes abscisic acid-responsive element (ABRE)-binding factors (ABFs) involved in abiotic stress tolerance. The expression of OsbZIP42 was induced by ABA treatment, although it was not induced by drought and salt stresses. Unlike other bZIP TFs, OsbZIP42 contained two transcriptional activation domains. Although the full-length OsbZIP42 protein did not, the N-terminus of the protein interacted with SAPK4. Our results suggest that the activation of OsbZIP42 by SAPK4 requires another ABA-dependent modification of OsbZIP42. Transgenic rice overexpressing OsbZIP42 (OsbZIP42-OX) exhibited a rapidly elevated expression of the ABA-responsive LEA3 and Rab16 genes and was hypersensitive to ABA. Analyses of the OsbZIP42-OX plants revealed enhanced tolerance to drought stress. These results suggest that OsbZIP42 is a positive regulator of ABA signaling and drought stress tolerance depending on its activation, which is followed by an additional ABA-dependent modification. We propose that OsbZIP42 is an important player in rice for conferring ABA-dependent drought tolerance.

Interplay between early-life malnutrition, epigenetic modulation of the immune function and liver diseases.

Early-life nutrition plays a critical role in fetal growth and development. Food intake absence and excess are the two main types of energy malnutrition that predispose to the appearance of diseases in adulthood, according to the hypothesis of 'developmental origins of health and disease'. Epidemiological data have shown an association between early-life malnutrition and the metabolic syndrome in later life. Evidence has also demonstrated that nutrition during this period of life can affect the development of the immune system through epigenetic mechanisms. Thus, epigenetics has an essential role in the complex interplay between environmental factors and genetics. Altogether, this leads to the inflammatory response that is commonly seen in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome. In conjunction, DNA methylation, covalent modification of histones and the expression of non-coding RNA are the epigenetic phenomena that affect inflammatory processes in the context of NAFLD. Here, we highlight current understanding of the mechanisms underlying developmental programming of NAFLD linked to epigenetic modulation of the immune system and environmental factors, such as malnutrition.

The activating protein 1 transcription factor basic leucine zipper transcription factor, ATF-like (BATF), regulates lymphocyte- and mast cell-driven immune responses in the setting of allergic asthma.

BACKGROUND: Mice without the basic leucine zipper transcription factor, ATF-like (BATF) gene (Batf(-/-)) lack TH17 and follicular helper T cells, which demonstrates that Batf is a transcription factor important for T- and B-cell differentiation. OBJECTIVE: In this study we examined whether BATF expression would influence allergic asthma. METHODS: In a cohort of preschool control children and children with asthma, we analyzed BATF mRNA expression using real-time PCR in PBMCs. In a murine model of allergic asthma, we analyzed differences in this allergic disease between wild-type, Batf transgenic, and Batf(-/-) mice. RESULTS: In the absence of corticosteroid treatment, children with recurrent asthma have a significant increase in BATF mRNA expression in their PBMCs. Batf(-/-) mice display a significant reduction in the pathophysiologic responses seen in asthmatic wild-type littermates. Moreover, we discovered a decrease in IL-3 production and IL-3-dependent mast cell development in Batf(-/-) mice. By contrast, IFN-γ was induced in lung CD4(+) and CD8(+) T cells. Intranasal delivery of anti-IFN-γ antibodies induced airway hyperresponsiveness and inflammation in wild-type but not in Batf(-/-) mice. Transgenic overexpression of Batf under the control of the CD2 promoter/enhancer augmented lung inflammation and IgE levels in the setting of experimental asthma. CONCLUSION: BATF is increased in non-steroid-treated asthmatic children. Targeting BATF expression resulted in amelioration of the pathophysiologic responses seen in children with allergic asthma, and BATF has emerged as a novel target for antiasthma interventions.

Dendritic cells in liver injury and fibrosis: shortcomings and promises.

The phenotype and function of liver dendritic cells (LDCs) are poorly understood. This Snapshot summarizes our current knowledge on LDCs in the healthy and injured liver, and their role in fibrosis progression and reversal. It also draws attention to various pitfalls in the current experimental design and conclusions based on available data.

Substrate profiling of the Arabidopsis Ca2+-dependent protein kinase AtCPK4 and its Ricinus communis ortholog RcCDPK1.

AtCPK4 and AtCPK11 are Arabidopsis thaliana Ca2+-dependent protein kinase (CDPK) paralogs that have been reported to positively regulate abscisic acid (ABA) signal transduction by phosphorylating ABA-responsive transcription factor-4 (AtABF4). By contrast, RcCDPK1, their closest Ricinus communis ortholog, participates in the control of anaplerotic carbon flux in developing castor oil seeds by catalyzing inhibitory phosphorylation of bacterial-type phosphoenolpyruvate carboxylase at Ser451. LC-MS/MS revealed that AtCPK4 and RcCDPK1 transphosphorylated several common, conserved residues of AtABF4 and its castor ortholog, TRANSCRIPTION FACTOR RESPONSIBLE FOR ABA REGULATON. Arabidopsis atcpk4/atcpk11 mutants displayed an ABA-insensitive phenotype that corroborated the involvement of AtCPK4/11 in ABA signaling. A kinase-client assay was employed to identify additional AtCPK4/RcCDPK1 targets. Both CDPKs were separately incubated with a library of 2095 peptides representative of Arabidopsis protein phosphosites; five overlapping targets were identified including PLANT INTRACELLULAR RAS-GROUP-RELATED LEUCINE-RICH REPEAT PROTEIN-9 (AtPIRL9) and the E3-ubiquitin ligase ARABIDOPSIS TOXICOS EN LEVADURA 6 (AtATL6). AtPIRL9 and AtATL6 residues phosphorylated by AtCPK4/RcCDPK1 conformed to a CDPK recognition motif that was conserved amongst their respective orthologs. Collectively, this study provides evidence for novel AtCPK4/RcCDPK1 substrates, which may help to expand regulatory networks linked to Ca2+- and ABA-signaling, immune responses, and central carbon metabolism.

Diagnostic and prognostic role of basic leucine zipper transcription factor in kidney renal clear cell carcinoma.

Background: Basic leucine zipper transcription factor (BATF) plays a crucial role in development and progression of different types of carcinomas. However, its prognostic value in kidney renal clear cell carcinoma (KIRC) is yet to be elucidated. Methods: We obtained clinicopathological data and expression profiles of BATF from The Cancer Genome Atlas (TCGA) on the pan-cancer and KIRC perspectives. We calculated the area under the curve (AUC) of the receiver-operating characteristic curves to understand the discriminatory capacity of BATF. Next, we generated Kaplan-Meier curves to assess the effect of BATF on the overall survival (OS) of patients, then performed univariate and multivariate Cox regression analyses. Subsequently, we used multivariate regression to construct a nomogram for predicting prognosis. Furthermore, we construct a protein-protein interaction (PPI) network, then performed gene set enrichment and pathway enrichment analyses to determine the biological function of the co-expression genes. Finally, we performed tumor microenvironment analyses to establish the relationship between BATF expression and infiltrating immune cells. Results: BATF was significantly upregulated in KIRC relative to normal kidney tissues. Upregulation of BATF mRNA was associated with higher TNM pathological stage, histological grade, and poor OS/PFI (progression-free interval). Receiver-operating characteristic (ROC) curves showed that BATF had excellent diagnostic value in KIRC, as evidenced by the AUC and cutoff values of 0.942 and 2.033, respectively. Kaplan-Meier survival curves demonstrated that KIRC patients with high-BATF were associated with worse prognosis (hazard ratio =1.42, P=0.024). Results from Cox univariate analyses indicated that BATF was an independent prognostic factor in KIRC patients, and survival probabilities were predicted by the established nomogram. Results from the Tumor Immune Estimation Resource (TIMER) and BATF mRNA expression showed an association with immune cell infiltration. Conclusions: BATF is a prognostic biomarker and a potential target for immune therapies in KIRC.

Heme oxygenase-1 induction by heat shock in rat hepatoma cell line is regulated by the coordinated function of HSF1, NRF2 and BACH1.

The mechanism of heme oxygenase-1 (HO-1) induction by heat shock (HS) loading remains unclear. Here, we investigated the contribution of transcription factors to HS-induced HO-1 expression, using a rat hepatoma cell line (H-4-II-E). Our results demonstrated that HS treatment resulted in a marked induction of HO-1. Immunohistochemical analysis showed a slight mismatch in the expression levels of HO-1 and HSP70 by HS among cells, suggesting a conflict between multiple induction mechanisms. We observed HS-induced nuclear localization of, not only phosphorylated HSF1 but also NRF2, which is a typical transcription factor activated by oxidative stress. HSF1 knockdown in H-4-II-E markedly reduced HO-1 induction by HS, while NRF2 knockdown resulted in a partial effect. The chromatin immunoprecipitation assay demonstrated that HS loading resulted in significant binding of HSF1 to the HSE in the promoter proximal region of HO-1 gene and another HSE located close to the Maf recognition element (MARE) in the -4 kb upstream enhancer region 1, where NRF2 also bound, together with basic leucine zipper transcription factor 1, a negative transcription factor of HO-1. These observations indicate that HO-1 induction by HS is mainly mediated by HSF1 binding to the proximal HSE. NRF2 binding to MARE by HS is predominantly suppressed by an increased binding of BACH1.

MeABL5, an ABA Insensitive 5-Like Basic Leucine Zipper Transcription Factor, Positively Regulates MeCWINV3 in Cassava (Manihot esculenta Crantz).

The basic leucine zipper (bZIP) transcription factor family plays crucial roles in multiple biological processes, especially stress responses. Cassava (Manihot esculenta Crantz) is an important tropical crop with a strong tolerance to environmental stresses such as drought, heat, and low-fertility environments. Currently, limited information is available regarding the functional identification of bZIP transcription factors in response to abiotic stress in cassava. Herein, a gene encoding an ABA Insensitive 5 (ABI5)-like transcription factor, designated as MeABL5, was identified in cassava. Sequence and phylogenetic analysis showed that MeABL5 is a cassava bZIP transcription factor that is not included in the previously identified cassava bZIP family members, belongs to subfamily A, and has high sequence similarity to ABI5-like proteins. Subcellular localization and transactivation assays revealed that MeABL5 was a nuclear-localized protein and possessed transactivation activity. Furthermore, MeABL5 was able to specifically interact with the ABRE cis-element in the promoter of the cassava major cell wall invertase gene, MeCWINV3, in vitro and in vivo. MeABL5 and MeCWINV3 exhibited similar expression patterns in various organs or tissues and under abiotic stress in cassava. The expressions of MeABL5 and MeCWINV3 within cassava plantlets were both induced by exogenous abscisic acid (ABA), gibberellic acid (GA3), methyl jasmonate (MeJA), and heat. Overexpression of MeABL5 increased the activity of the MeCWINV3 gene, and the up-regulated expressions of MeCWINV3 were significantly activated under ABA-, salicylic acid (SA)-, and MeJA-induced conditions. Overall, these results suggest that MeABL5 is a positive regulator of MeCWINV3 and might participate in the robust resistance of cassava in response to abiotic stress. This study also provides a foundation for further research on ABA-mediated and stress-related signaling pathways in cassava.

BATF regulates collagen-induced arthritis by regulating T helper cell differentiation.

BACKGROUND: We recently demonstrated that BATF, a member of the activator protein-1 (AP-1) family, regulates osteoarthritic cartilage destruction. Here, we explored the roles and regulatory mechanisms of BATF in collagen-induced arthritis (CIA) in mice. METHODS: CIA and K/BxN serum transfer were used to generate inflammatory arthritis models in wild-type (WT) and Batf-/- mice. RA manifestations were determined by examining CIA incidence, clinical score, synovitis, synovial hyperplasia, angiogenesis in inflamed synovium, pannus formation, bone erosion, and cartilage destruction. Immune features in RA were analyzed by examining immune cell populations and cytokine production. RESULTS: BATF was upregulated in the synovial tissues of joints in which inflammatory arthritis had been caused by CIA or K/BxN serum transfer. The increases in CIA incidence, clinical score, and autoantibody production in CIA-induced WT mice were completely abrogated in the corresponding Batf-/- DBA/1 J mice. Genetic ablation of Batf also inhibited CIA-induced synovitis, synovial hyperplasia, angiogenesis in synovial tissues, pannus formation, bone erosion, and cartilage destruction. Batf knockout inhibited the differentiation of T helper (Th)17 cells and the conversion of CD4+Foxp3+ cells to CD4+IL-17+ cells. However, BATF did not modulate the functions of fibroblast-like synoviocytes (FLS), including the expressions of chemokines, matrix-degrading enzymes, vascular endothelial growth factor, and receptor activator of NF-κB ligand (RANKL). CONCLUSION: Our findings indicate that BATF crucially mediates CIA by regulating Th cell differentiation without directly affecting the functions of FLS.

Increased BATF expression is associated with the severity of liver damage in patients with chronic hepatitis B.

T helper (Th) 17 cells have a critical role in the pathogenesis of chronic hepatitis B virus (HBV) infection, and basic leucine zipper transcription factor, ATF-like (BATF) is a newly identified transcriptional factor regulating the differentiation of Th17 cells. However, its precise role in patients with chronic hepatitis B remains unclear. Sixty chronic hepatitis B (CHB) patients, twenty-two acute-on-chronic hepatitis B liver failure (ACHBLF) patients and seventeen healthy controls were included in our study. Both peripheral and intrahepatic expressions of BATF were analyzed by flow cytometry, quantitative real-time polymerase chain reaction and immunohistochemical staining. Peripheral BATF mRNA and protein expression levels were higher in CHB patients than those in healthy controls. Particularly in ACHBLF patients, the BATF mRNA and protein levels were further increased over those in CHB patients. Intrahepatic BATF-positive infiltrating cells were enriched in portal area of CHB patients, and more positive cells were found in patients with higher inflammation grade. Peripheral BATF expression was positively correlated with serum parameters of liver injury and plasma HBV DNA load. Furthermore, a positive correlation was found between the frequency of BATF-positive CD3+ T cells and the increased Th17 response in chronic HBV-infected patients. BATF over-expression might augment Th17 cell response and relate to the disease progression of CHB.

Targeting Inflammatory T Helper Cells via Retinoic Acid-Related Orphan Receptor Gamma t Is Ineffective to Prevent Allo-Response-Driven Colitis.

Intestinal graft-versus-host disease (GvHD) is a life-threatening, inflammatory donor T cell-mediated complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the light of the reported efficacy of interleukin-23 (IL-23)-blockade to mitigate syngeneic intestinal inflammation in inflammatory bowel disease patients, targeting IL-23 and thereby interleukin-17a (IL-17a) producing T helper (Th17) cells as the T cell subset assumed to be mostly regulated by IL-23, has emerged as a putatively general concept to harness immune-mediated mucosal inflammation irrespective of the underlying trigger. However, the role of Th17 cells during allo-response driven colitis remains ambiguous due to a series of studies with inconclusive results. Interestingly, we recently identified granulocyte-macrophage colony-stimulating factor (GM-CSF+) T cells to be promoted by interleukin-7 (IL-7) signaling and controlled by the activating protein-1 transcription factor family member basic leucine zipper transcription factor ATF-like (BATF) as critical mediators of intestinal GvHD in mice. Given the dual role of BATF, the contribution of IL-23-mediated signaling within donor T cells and bona fide Th17 cells remains to be delineated from the regulation of GM-CSF+ T cells in the absence of BATF. Here, we found in a complete MHC class I-mismatched model that genetic inactivation of the IL-23 receptor (IL-23R) or the transcription factor retinoic acid-related orphan receptor gamma t (RORγt) within donor T cells similarly ablated Th17 cell formation in vivo but preserved the T cells' ability to induce intestinal GvHD in a compared to wild-type controls indistinguishable manner. Importantly, RORγt-independent manifestation of intestinal GvHD was completely dependent on BATF-regulated GM-CSF+ T cells as BATF/RORγt double-deficient T cells failed to induce colitis and the antibody-mediated blockage of IL-7/IL-7R interaction and GM-CSF significantly diminished signs of intestinal GvHD elicited by RORγt-deficient donor T cells. Finally, in analogy to our murine studies, colonic RORC expression levels inversely correlated with the presence of GvHD in allo-HSCT patients. Together, this study provides a crucial example of a BATF-dependent, however, IL-23R signaling- and RORγt-, i.e., Th17 fate-independent regulation of a colitogenic T cell population critically impacting the current understanding of intestinal GvHD.

Cis-element of the rice PDIL2-3 promoter is responsible for inducing the endoplasmic reticulum stress response.

A protein disulfide isomerase (PDI) family oxidoreductase, PDIL2-3, is involved in endoplasmic reticulum (ER) stress responses in rice. We identified a critical cis-element required for induction of the ER stress response. The activation of PDIL2-3 in response to ER stress strongly depends on the IRE1-OsbZIP50 signaling pathway.

Arsenic exposure triggers a shift in microRNA expression.

Exposure to inorganic Arsenic (iAs) through drinking water is a major public health problem affecting most countries. iAs has been classified by the International Agency for Research on Cancer as Group 1: "Carcinogenic to humans". Although numerous studies have shown the related adverse effects of iAs, sensitive appropriate biomarkers for studies of environmental epidemiology are still required. The present work aims at investigate the role of microRNAs (miRNAs), powerful negative regulators of gene expression, playing a key role in many physiological and pathological cellular processes, in iAs exposure. To this end, we analyzed miRNA changes in expression profile triggered by iAs exposure in Jurkat cell line. We used microarray technology to profile the expression of miRNAs following 2 µmol/L sodium arsenite treatment at different time points. Moreover, we performed phenotypic analysis of iAs treated cells. Real Time Polymerase Chain Reaction (RT-PCR) was used to validate miRNA microarray data and to assay expression modulation of selected relevant mRNAs. Finally, bioinformatics techniques were applied to reconstruct iAs-relevant molecular pathways and miRNA regulatory networks from the expression data. We report miRNAs modulated after iAs treatment in Jurkat cells. In particular, we highlight 36 miRNAs exhibiting consistent dysregulation and particularly a panel of 8 miRNAs which we also validated by RT-PCR analysis. Computational analysis of lists of putative target genes for these 8 miRNAs points to an involvement in arsenic-response pathways, for a subset of them, that were analyzed by RT-PCR. Furthermore, iAs exposure reveals induction of cell cycle progression and the failure of apoptosis, supporting the idea of iAs carcinogenic activity. Our study provides a list of miRNAs whose expression levels are affected by iAs treatment, corroborating the importance of proceeding with the hunt for specific subset of miRNAs, which can serve as potential biomarkers of iAs effects with useful diagnostic value.