Endogenous Suppressor Research Articles

Bilirubin represents a negative regulator of ILC2 in allergic airway inflammation.

Group 2 innate lymphoid cells (ILC2s) play an important role in allergic airway inflammation. Despite recent advances in defining molecular mechanisms that control ILC2 development and function, the role of endogenous metabolites in the regulation of ILC2s remains poorly understood. Herein, we demonstrated that bilirubin, an end product of heme catabolism, was a potent negative regulator of ILC2s. Bilirubin metabolism was found to be significantly induced during airway inflammation in mouse models. The administration of unconjugated bilirubin (UCB) dramatically suppressed ILC2 responses to interleukin (IL)-33 in mice, including cell proliferation and the production of effector cytokines. Furthermore, UCB significantly alleviated ILC2-driven airway inflammation, which was aggravated upon clearance of endogenous UCB. Mechanistic studies showed that the effects of bilirubin on ILC2s were associated with downregulation of ERK phosphorylation and GATA3 expression. Clinically, newborns with hyperbilirubinemia displayed significantly lower levels of ILC2 with impaired function and suppressed ERK signaling. Together, these findings indicate that bilirubin serves as an endogenous suppressor of ILC2s and might have potential therapeutic value in the treatment of allergic airway inflammation.

Hepatocyte glutathione S-transferase mu 2 prevents non-alcoholic steatohepatitis by suppressing ASK1 signaling

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. The advanced stage of NAFLD, non-alcoholic steatohepatitis (NASH), has been recognized as a leading cause of end-stage liver injury for which there are no FDA-approved therapeutic options. Glutathione S-transferase Mu 2 (GSTM2) is a phase II detoxification enzyme. However, the roles of GSTM2 in NASH have not been elucidated. Multiple RNA-seq analyses were used to identify hepatic GSTM2 expression in NASH. Invitro and invivo gain- or loss-of-function approaches were used to investigate the role and molecular mechanism of GSTM2 in NASH. We identified GSTM2 as a sensitive responder and effective suppressor of NASH progression. GSTM2 was significantly downregulated during NASH progression. Hepatocyte GSTM2 deficiency markedly aggravated insulin resistance, hepatic steatosis, inflammation and fibrosis induced by a high-fat diet and a high-fat/high-cholesterol diet. Mechanistically, GSTM2 sustained MAPK pathway signaling by directly interacting with apoptosis signal-regulating kinase 1 (ASK1). GSTM2 directly bound to the N-terminal region of ASK1 and inhibited ASK1 N-terminal dimerization to subsequently repress ASK1 phosphorylation and the activation of its downstream JNK/p38 signaling pathway under conditions of metabolic dysfunction. These data demonstrated that hepatocyte GSTM2 is an endogenous suppressor that protects against NASH progression by blocking ASK1 N-terminal dimerization and phosphorylation. Activating GSTM2 holds promise as a therapeutic strategy for NASH. IIT-2021-277. New therapeutic strategies for non-alcoholic steatohepatitis are urgently needed. We identified that the protein GSTM2 exerts a protective effect in response to metabolic stress. Therapies that aim to increase the activity of GSTM2 could hold promise for the treatment of non-alcoholic steatohepatitis.

1178P Senescence signature affects overall survival in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, with adenocarcinoma as the most common histological type. Cellular senescence (CS) is a durable and generally irreversible cell cycle arrest with secretory features, macromolecular damage and altered metabolism elicited in response to different stresses (e.g., DNA damage), and it is generally considered as an endogenous tumor suppressor mechanism. However, senescent cancer cells stay metabolically active and can secrete a plethora of cytokines, growth factors and proteases that can affect the surrounding tumor microenvironment, ultimately leading to cancer relapse and metastasis.

Transcriptional downregulation of FAM3C/ILEI in the Alzheimer's brain.

Amyloid-β (Aβ) accumulation in the brain triggers the pathogenic cascade for Alzheimer's disease (AD) development. The secretory protein FAM3C (also named ILEI) is a candidate for an endogenous suppressor of Aβ production. In this study, we found that FAM3C expression was transcriptionally downregulated in the AD brain. To determine the transcriptional mechanism of the human FAM3C gene, we delineated the minimal 5'-flanking sequence required for basal promoter activity. From a database search for DNA-binding motifs, expression analysis using cultured cells, and promoter DNA-binding assays, we identified SP1 and EBF1 as candidate basal transcription factors for FAM3C, and found that SMAD1 was a putative inducible transcription factor and KLF6 was a transcription repressor for FAM3C. Genomic deletion of the basal promoter sequence from HEK293 and Neuro-2a cells markedly reduced endogenous expression of FAM3C and abrogated SP1- or EBF1-mediated induction of FAM3C. Nuclear protein extracts from AD brains contained lower levels of SP1 and EBF1 than did those from control brains, although the relative mRNA levels of these factors did not differ significantly between the groups. Additionally, the ability of nuclear SP1 and EBF1 in AD brains to bind with the basal promoter sequence-containing DNA probe was reduced compared with the binding ability of these factors in control brains. Thus, the transcriptional downregulation of FAM3C in the AD brain is attributable to the reduced nuclear levels and genomic DNA binding of SP1 and EBF1. An expressional decline in FAM3C may be a risk factor for Aβ accumulation and eventually AD development.

MICAL2PV suppresses the formation of tunneling nanotubes and modulates mitochondrial trafficking.

Tunneling nanotubes (TNTs) are actin‐rich structures that connect two or more cells and mediate cargo exchange between spatially separated cells. TNTs transport signaling molecules, vesicles, organelles, and even pathogens. However, the molecular mechanisms regulating TNT formation remain unclear and little is known about the endogenous mechanisms suppressing TNT formation in lung cancer cells. Here, we report that MICAL2PV, a splicing isoform of the neuronal guidance gene MICAL2, is a novel TNT regulator that suppresses TNT formation and modulates mitochondrial distribution. MICAL2PV interacts with mitochondrial Rho GTPase Miro2 and regulates subcellular mitochondrial trafficking. Moreover, down‐regulation of MICAL2PV enhances survival of cells treated with chemotherapeutical drugs. The monooxygenase (MO) domain of MICAL2PV is required for its activity to inhibit TNT formation by depolymerizing F‐actin. Our data demonstrate a previously unrecognized function of MICAL2 in TNT formation and mitochondrial trafficking. Furthermore, our study uncovers a role of the MICAL2PV‐Miro2 axis in mitochondrial trafficking, providing a mechanistic explanation for MICAL2PV activity in suppressing TNT formation and in modulating mitochondrial subcellular distribution.

A phase II trial of abemaciclib in patients with p16ink4a negative, relapsed mesothelioma.

8558 Background: Genetically stratified therapy for malignant mesothelioma (MM) is lacking. MMs frequently harbour loss of chromosome 9p21.3 locus (CDKN2A) associated with shorter survival. CDKN2A encodes the tumour suppressor p16ink4a, an endogenous suppressor of CDK4 and CDK6. Genetic reconstitution of p16ink4a into CDKN2A suppresses MM in preclinical models, underpinning the rationale for targeting of CDK4/6 in p16ink4a negative MM. We therefore developed a multi-centre molecularly stratified phase IIa trial to test this hypothesis as arm 2 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST2). Methods: Patients with histologically confirmed MM (pleural or peritoneal) were molecularly screened by immunohistochemistry for p16ink4a, BAP1, BRCA1, and PDL1 (Dako 22C3). Patients with p16ink4a negative MM were eligible. Key inclusion factors: histological confirmation of MM with an available archival tissue block, ECOG performance status 0-1, prior platinum-based 1st line chemotherapy (any line allowed), evidence of disease progression with measurable disease by CT (RECIST 1.1), and adequate haematological/organ function. Patients received Abemaciclib (Ab) 200mg bd po daily in q21 day cycles. Primary endpoint was disease control rate at 12 weeks (DCR12w). The null hypothesis was rejected if ≥ 11 patients had disease control (A’Hern design). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate and toxicity (NCI CTCAE 4.03). Patients could undergo an optional re-biopsy upon disease progression. Results: Between November 2019 and March 2020, 26 patients with p16ink4a negative MM received at least one dose of Ab. The median age of pts was 67 (range, 64-74) years, 89% were male, 80.8% epithelioid, 84.6% ECOG PS1, > 1 prior systemic therapy 62%. All patients received at least one cycle with 27% completing 6 cycles. No dose reductions occurred in 53.9% of pts. DCR12w: 54% (95% confidence limit (CI), 36% – 71%), DCR24w: 23% (95%CI, 9% – 44%). Best responses (within 24w): partial - 15% (95%CI, 4- 35%), one occurring after 18 weeks; stable disease - 53.8% (33.4 – 73.4%); progression - 7.7% (0.9 – 25.1%). Adverse events (any cause): ≥ grade 3 toxicities affected 5.7% of pts. Conclusions: MiST2 met its primary endpoint, warranting further clinical evaluation of Ab. Whole exome sequencing of the cohort is ongoing to explore genomic correlates of de novo and acquired resistance. Clinical trial information: NCT03654833.

Countering Inflammatory Arthritis by 14-3-3zeta: A Novel Target

Abstract Inflammatory arthritis (IA) is a common inflammatory joint-destructive condition that affects millions of individuals worldwide. Increased immune dysfunction and bone loss have been observed both in IA affected humans and in animal models. Proinflammatory events responsible for RA pathogenesis have been studied in detail; however, the protective mechanism remains under-explored. Earlier, we reported that 14-3-3zeta (z) is a molecular determinant of skewing T cell polarization and interleukin-17A (IL-17A) signal transduction. Here we demonstrate that 14-3-3z is an endogenous suppressor of IA. Loss of 14-3-3z in a novel CRISPR/Cas9 edited knockout (KO) rat resulted in early-onset and severe arthritis in animal models of inflammatory arthritis. Arthritic 14-3-3z KO animals showed increased bone loss and immune cell infiltration in synovial joints. Rescue experiments to supplement the 14-3-3z by immunization during the pre-symptomatic phase resulted in significant arthritis suppression in both wild-type and 14-3-3z KO rats. Immunization generated a robust increase in 14-3-3z antibody and IL-17A, suppressed several cytokines, including IFN-g, TNF-a, and Cxcl-1, preserved tissue mineral bone density, and trabecular bone volume. Our findings, taken together with the prior report of the molecular function of 14-3-3z as an antigen, indicate that antigenic 14-3-3z is responsible for a previously unrecognized inflammatory arthritis-suppressive mechanism.

Role and mechanism of TXNIP in ageing-related renal fibrosis

Kidney ageing, which is always accompanied by renal fibrosis, drives the progression of renal fibrosis. Thioredoxin-interacting protein (TXNIP) is an endogenous suppressor of the reactive oxygen species-scavenging protein thioredoxin, which has been implicated in the ageing of some organs and is involved in renal fibrosis. However, the expression of TXNIP in ageing kidneys has not been examined, and the relationship between TXNIP and ageing-related renal fibrosis is unclear. We found that TXNIP expression was upregulated in aged mouse kidneys, and this upregulation was accompanied by ageing-related renal fibrosis phenotypes. We demonstrated that the ageing biomarkers were downregulated in TXNIP-knockout mice, and these effects resulted in the alleviation of renal fibrosis and impairments in kidney function. TXNIP overexpression in tubular cells upregulated senescence markers, promoted a profibrotic response and activated STAT3 signalling, and these parameters were inhibited by the silencing of TXNIP. Similarly, the TXNIP-mediated profibrotic response was significantly suppressed by a STAT3 inhibitor. By coimmunoprecipitation, we verified that TXNIP directly bound to STAT3, which suggested that TXNIP exacerbates renal tubular epithelial fibrosis by activating the STAT3 pathway. In summary, TXNIP plays an important role in age-related renal fibrosis and might be a therapeutic target for preventing ageing-associated renal fibrosis.

Extracellular Release of ILEI/FAM3C and Amyloid-β Is Associated with the Activation of Distinct Synapse Subpopulations.

Brain amyloid-β (Aβ) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and Aβ deposition in Alzheimer's disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for Aβ generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous Aβ suppressor. This study aimed to access the mechanism underlying ILEI secretion and its effect on Aβ production in the brain. ILEI and Aβ levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis in mutant human Aβ precursor protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA. Extracellular release of ILEI and Aβ was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and Aβ revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of Aβ levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and Aβ levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of Aβ and were reduced in AD and mild cognitive impairment. ILEI and Aβ are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates Aβ production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain Aβ.

Diagnostic and Therapeutic Implications of microRNAs in Non-Small Cell Lung Cancer.

microRNAs (miRNAs), endogenous suppressors of target mRNAs, are deeply involved in every step of non-small cell lung cancer (NSCLC) development, from tumor initiation to progression and metastasis. They play roles in cell proliferation, apoptosis, angiogenesis, epithelial-to-mesenchymal transition, migration, invasion, and metastatic colonization, as well as immunosuppression. Due to their versatility, numerous attempts have been made to use miRNAs for clinical applications. miRNAs can be used as cancer subtype classifiers, diagnostic markers, drug-response predictors, prognostic markers, and therapeutic targets in NSCLC. Many challenges remain ahead of their actual clinical application; however, when achieved, the use of miRNAs in the clinic is expected to enable great progress in the diagnosis and treatment of patients with NSCLC.

14-3-3ζ–TRAF5 axis governs interleukin-17A signaling

IL-17A is a therapeutic target in many autoimmune diseases. Most nonhematopoietic cells express IL-17A receptors and respond to extracellular IL-17A by inducing proinflammatory cytokines. The IL-17A signal transduction triggers two broad, TRAF6- and TRAF5-dependent, intracellular signaling pathways to produce representative cytokines (IL-6) and chemokines (CXCL-1), respectively. Our limited understanding of the cross-talk between these two branches has generated a crucial gap of knowledge, leading to therapeutics indiscriminately blocking IL-17A and global inhibition of its target genes. In previous work, we discovered an elevated expression of 14-3-3 proteins in inflammatory aortic disease, a rare human autoimmune disorder with increased levels of IL-17A. Here we report that 14-3-3ζ is essential for IL-17 signaling by differentially regulating the signal-induced IL-6 and CXCL-1. Using genetically manipulated human and mouse cells, and ex vivo and in vivo rat models, we uncovered a function of 14-3-3ζ. As a part of the molecular mechanism, we show that 14-3-3ζ interacts with several TRAF proteins; in particular, its interaction with TRAF5 and TRAF6 is increased in the presence of IL-17A. In contrast to TRAF6, we found TRAF5 to be an endogenous suppressor of IL-17A-induced IL-6 production, an effect countered by 14-3-3ζ. Furthermore, we observed that 14-3-3ζ interaction with TRAF proteins is required for the IL-17A-induced IL-6 levels. Together, our results show that 14-3-3ζ is an essential component of IL-17A signaling and IL-6 production, an effect that is suppressed by TRAF5. To the best of our knowledge, this report of the 14-3-3ζ-TRAF5 axis, which differentially regulates IL-17A-induced IL-6 and CXCL-1 production, is unique.

MiR-944/CISH mediated inflammation via STAT3 is involved in oral cancer malignance by cigarette smoking

The cytokine-inducible Src homology 2-containing protein (CISH) is an endogenous suppressors of signal transduction and activator of transcription (STAT) and acts as a key negative regulator of inflammatory cytokine responses. Downregulation of CISH has been reported to associate with increased activation of STAT and enhanced inflammatory pathways. However, whether microRNAs (miRNAs) play a crucial role in CISH/STAT regulation in oral squamous cell carcinoma (OSCC) remains unknown. The expression of CISH on OSCC patients was determine by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Specific targeting by miRNAs was determined by software prediction, luciferase reporter assay, and correlation with target protein expression. The functions of miR-944 and CISH were accessed by transwell migration and invasion analyses using gain- and loss-of-function approaches. Enzyme-linked immunosorbent assay (ELISA) and qRT-PCR were used to evaluate the pro-inflammation cytokines expression under the miR-944, CISH, NNK or combinations treatment. We found that the CISH protein, which modulates STAT3 activity, as a direct target of miR-944. CISH protein was significantly down-regulated in OSCC patients and cell lines and its level was inversely correlated with miR-944 expression. The miR-944-induced STAT3 phosphorylation, pro-inflammation cytokines secretion, migration and invasion were abolished by CISH restoration, suggesting that the oncogenic activity of miR-944 is CISH dependent. Furthermore, tobacco extract (NNK) may contribute to miR-944 induction and STAT3 activation. Antagomir-mediated inactivation of miR-944 prevented the NNK-induced STAT3 phosphorylation and pro-inflammation cytokines secretion. Altogether, these data demonstrate that NNK-induced miR944 expression plays an important role in CISH/STAT3-mediated inflammatory response and activation of tumor malignancy.

The clinicopathological and prognostic implications of tyrosine phosphatase SHP2 and ankyrin Hook1 gene expression in non- small cell lung cancer patients treated with gemcitabine plus platinum as first-line chemotherapy.

SHP2, a widely expressed phosphatase, which has been linked to the initiation, progression and prognosis of various malignancies. We previously identified a new SHP2 anchorage protein Hook1 in the alveolar II epithelial cells, and it is suggested that Hook1 is a novel endogenous suppressor molecule of SHP2 phosphatase activity. Nevertheless, few studies have been mentioned the clinicopathological and prognostic relevance of SHP2 and Hook1 expression in patients with non-small cell lung cancer (NSCLC). A total of 61 patients with NSCLC receiving gemcitabine plus carboplatin chemotherapy were studied. Immunohistochemical staining was conducted to determine the protein expression of SHP2 and Hook1. The relationships between gene expression and clinical and pathological factors, as well as prognosis, were evaluated. A significant correlation was observed between the SHP2 and Hook1 expression, with a total expression rate of 71.4%. The positive expression of Hook1 in adenocarcinoma and in stage IIIb-IV was higher than that in patients with squamous (73.5% vs. 31.2%, P=0.013) and I-IIIa (75% vs. 48.8%, P=0.05), suggesting that Hook1 might act as an indicator of NSCLC status. However, no significant correlation was observed between Hook1 expression and survival time (P>0.05). In contrast, patients with negative SHP2 expression had a higher survival rate (median overall survival 68 vs. 24 months, P=0.003). Cox multivariate regression analysis showed that SHP2 was an independent indicator for overall survival (P=0.009). The present study suggested that NSCLC patients with negative SHP2 expression could benefit from gemcitabine plus carboplatin chemotherapy, and further study is needed to confirm the prognostic value of SHP2 and Hook1.

Therapeutic Zfra4-10 or WWOX7-21 Peptide Induces Complex Formation of WWOX with Selective Protein Targets in Organs that Leads to Cancer Suppression and Spleen Cytotoxic Memory Z Cell Activation In Vivo.

Synthetic Zfra4-10 and WWOX7-21 peptides strongly suppress cancer growth in vivo. Hypothetically, Zfra4-10 binds to the membrane Hyal-2 of spleen Z cells and activates the Hyal-2/WWOX/SMAD4 signaling for cytotoxic Z cell activation to kill cancer cells. Stimulation of membrane WWOX in the signaling complex by a WWOX epitope peptide, WWOX7-21, is likely to activate the signaling. Here, mice receiving Zfra4-10 or WWOX7-21 peptide alone exhibited an increased binding of endogenous tumor suppressor WWOX with ERK, C1qBP, NF-κB, Iba1, p21, CD133, JNK1, COX2, Oct4, and GFAP in the spleen, brain, and/or lung which led to cancer suppression. However, when in combination, Zfra4-10 and WWOX7-21 reduced the binding of WWOX with target proteins and allowed tumor growth in vivo. In addition to Zfra4-10 and WWOX7-21 peptides, stimulating the membrane Hyal-2/WWOX complex with Hyal-2 antibody and sonicated hyaluronan (HAson) induced Z cell activation for killing cancer cells in vivo and in vitro. Mechanistically, Zfra4-10 binds to membrane Hyal-2, induces dephosphorylation of WWOX at pY33 and pY61, and drives Z cell activation for the anticancer response. Thus, Zfra4-10 and WWOX7-21 peptides, HAson, and the Hyal-2 antibody are of therapeutic potential for cancer suppression.

NULP1 Alleviates Cardiac Hypertrophy by Suppressing NFAT3 Transcriptional Activity.

BackgroundThe development of pathological cardiac hypertrophy involves the coordination of a series of transcription activators and repressors, while their interplay to trigger pathological gene reprogramming remains unclear. NULP1 (nuclear localized protein 1) is a member of the basic helix‐loop‐helix family of transcription factors and its biological functions in pathological cardiac hypertrophy are barely understood.Methods and ResultsImmunoblot and immunostaining analyses showed that NULP1 expression was consistently reduced in the failing hearts of patients and hypertrophic mouse hearts and rat cardiomyocytes. Nulp1 knockout exacerbates aortic banding‐induced cardiac hypertrophy pathology, which was significantly blunted by transgenic overexpression of Nulp1. Signal pathway screening revealed the nuclear factor of activated T cells (NFAT) pathway to be dramatically suppressed by NULP1. Coimmunoprecipitation showed that NULP1 directly interacted with the topologically associating domain of NFAT3 via its C‐terminal region, which was sufficient to suppress NFAT3 transcriptional activity. Inactivation of the NFAT pathway by VIVIT peptides in vivo rescued the aggravated pathogenesis of cardiac hypertrophy resulting from Nulp1 deficiency.ConclusionsNULP1 is an endogenous suppressor of NFAT3 signaling under hypertrophic stress and thus negatively regulates the pathogenesis of cardiac hypertrophy. Targeting overactivated NFAT by NULP1 may be a novel therapeutic strategy for the treatment of pathological cardiac hypertrophy and heart failure.

Ethylene functions as a suppressor of volatile production in rice.

We examined the role of ethylene in the production of rice (Oryza sativa) volatile organic compounds (VOCs), which act as indirect defense signals against herbivores in tritrophic interactions. Rice plants were exposed to exogenous ethylene (1 ppm) after simulated herbivory, which consisted of mechanical wounding supplemented with oral secretions (WOS) from the generalist herbivore larva Mythimna loreyi. Ethylene treatment highly suppressed VOCs in WOS-treated rice leaves, which was further corroborated by the reduced transcript levels of major VOC biosynthesis genes in ethylene-treated rice. In contrast, the accumulation of jasmonates (JA), known to control VOCs in higher plants, and transcript levels of primary JA response genes, including OsMYC2, were not largely affected by ethylene application. At the functional level, flooding is known to promote internode elongation in young rice via ethylene signaling. Consistent with the negative role of ethylene on VOC genes, the accumulation of VOCs in water-submerged rice leaves was suppressed. Furthermore, in mature rice plants, which naturally produce less volatiles, VOCs could be rescued by the application of the ethylene perception inhibitor 1-methylcyclopropene. Our data suggest that ethylene acts as an endogenous suppressor of VOCs in rice plants during development and under stress.

Programmed cell death 4 as an endogenous suppressor of BDNF translation is involved in stress-induced depression

Brain-derived neurotrophic factor (BDNF) is a growth factor that plays vital roles in the neuron survival, growth, and neuroplasticity. Alteration to BDNF expression is associated with major depressive disorder. However, the BDNF translational machinery in depression remains unknown. Herein, we pointed that Pdcd4, a suppressor oncogene, acted as an endogenous inhibitor for the translation of BDNF, and selectively repressed the translation of BDNF splice variant IIc mRNA in an eIF4A-dependent manner. Chronic restraint stress (CRS) up-regulated Pdcd4 expression in hippocampus via decreasing mTORC1-mediated proteasomes degradation pathway, which resulted in the reduction of BDNF protein expression. Moreover, over-expression of Pdcd4 in the hippocampus triggered spontaneous depression-like behaviors under the non-stressed conditions in mice, while systemic or neuron-specific knockout of Pdcd4 reverses CRS-induced depression-like behaviors. Importantly, administration of Pdcd4 siRNA or an interfering peptide that interrupts the Pdcd4-eIF4A complex substantially promoted BDNF expression and rescued the behavioral disorders which were caused by CRS. Overall, we have discovered a previously unrecognized role of Pdcd4 in controlling BDNF mRNA translation, and provided a new method that boosting BDNF expression through blocking the function of Pdcd4 in depression, indicating that Pdcd4 might be a new potential target for depressive disorder therapy.

<p>The lncRNA BCYRN1 Functions as an Oncogene in Human Glioma by Downregulating miR-125a-5p in vitro</p>

IntroductionNumerous studies have demonstrated that long noncoding RNAs (lncRNAs) are deregulated in many cancers and exert their functions through multiple cancer-related biological processes. Glioma is the most common primary malignant central nervous system tumor and has a high fatality rate in adults. In current study, we aimed to determine the role and functional mechanism of the lncRNA BCYRN1 in glioma.MethodsGain-of-function and loss-of function approaches were used to investigate the function of BCYRN1. The effects of BCYRN1 on glioma cell proliferation, migration and invasion were evaluated using MTS, Transwell and wound-healing assays. The correlation between the expression of BCYRN1 and miR-125a-5p was verified by quantitative real-time PCR.ResultsThe upregulation of BCYRN1 promoted the proliferation, migration and invasion of glioma cells. Meanwhile, the knockdown of BCYRN1 had the opposite effects. BCYRN1 was negatively correlated with miR-125a-5p. Additionally, TAZ, the endogenous target of miR-125a-5p, could be regulated by BCYRN1 in RNA and protein levels. A miR-125a-5p inhibitor restored BCYRN1 siRNA function in glioma.ConclusionThe present study indicates that BCYRN1 promotes glioma cell proliferation, invasion and migration in vitro. Mechanistically, upregulated expression of BCYRN1 in glioma acts as a sponge to sequester the endogenous tumor suppressor miR-125a-5p and to further increase the expression TAZ. Our findings suggest that BCYRN1 is a novel oncogene and a new therapeutic target for glioma.

Rice Stripe Mosaic Virus–Encoded P4 Is a Weak Suppressor of Viral RNA Silencing and Is Required for Disease Symptom Development

Viral suppressors of RNA silencing (VSRs) are a cluster of viral proteins that have evolved to counteract eukaryotic antiviral RNA silencing pathways, thereby contributing to viral pathogenicity. In this study, we revealed that the matrix protein P4 encoded by rice stripe mosaic virus (RSMV), which is an emerging cytoplasmic rhabdovirus, is a weak RNA silencing suppressor. By conducting yeast two-hybrid, bimolecular fluorescence complementation, and subcellular colocalization assays, we proved that P4 interacts with the rice endogenous suppressor of gene silencing 3 (OsSGS3). We also determined that P4 overexpression has no effect on OsSGS3 transcription. However, P4 can promote the degradation of OsSGS3 via ubiquitination and autophagy. Additionally, a potato virus X-based expression system was used to confirm that P4 enhances the development of mosaic symptoms on Nicotiana benthamiana leaves by promoting hydrogen peroxide accumulation but not cell death. To verify whether P4 is a pathogenicity factor in host plants, we generated transgenic P4-overexpressing rice plants that exhibited disease-related developmental defects including decreased plant height and excessive tillering. Our data suggest that RSMV-encoded P4 serves as a weak VSR that inhibits antiviral RNA silencing by targeting OsSGS3.

AIFM2 blocks ferroptosis independent of ubiquinol metabolism

Ferroptosis is a multi-step regulated cell death that is characterized by excessive iron accumulation and lipid peroxidation. Cancer cells can acquire resistance to ferroptosis by the upregulation of anti-ferroptotic proteins or by the downregulation of pro-ferroptotic proteins. Apoptosis-inducing factor mitochondria-associated 2 (AIFM2, also known as FSP1 or PRG3) has been recently demonstrated as an endogenous ferroptosis suppressor, but its mechanism remains obscure. Here, we show that AIFM2 blocks erastin-, sorafenib-, and RSL3-induced ferroptotic cancer cell death through a mechanism independent of ubiquinol, the reduced and active antioxidant form of coenzyme Q10. In contrast, AIFM2-dependent endosomal sorting complexes required for transport (ESCRT)-III recruitment in the plasma membrane is responsible for ferroptosis resistance through the activation of a membrane repair mechanism that regulates membrane budding and fission. Importantly, the genetic inhibition of the AIFM2-dependent ESCRT-III pathway increases the anticancer activity of sorafenib in a xenograft tumor mouse model. These findings shed new light on the mechanism involved in ferroptosis resistance during tumor therapy.