Targeting eIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer.

Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A with zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages toward an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade.

Targeting EIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer.

Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A by Zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages towards an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade.

Should App Self-Management Mean Self-Control? A Quantiative Study on App Supported Diabetes Self-Management.

Apps have been attested to empower patients regarding disease self-management through numerous studies. However, it is still unclear what factors determine the perception of patients whether an app is a useful tool for this purpose. A multiple regression model that was informed by the Technology Acceptance Model (TAM 2) was tested based on the answers of 235 app users with Diabetes type 1 or 2.

Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy.

Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease.

The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling.

Background & Aims: Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer-associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic.

Methods: We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls).

Expansion of germline RPS20 mutation phenotype to include Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a ribosomopathy of variable expressivity and penetrance characterized by red cell aplasia, congenital anomalies, and predisposition to certain cancers, including early-onset colorectal cancer (CRC). DBA is primarily caused by a dominant mutation of a ribosomal protein (RP) gene, although approximately 20% of patients remain genetically uncharacterized despite exome sequencing and copy number analysis. Although somatic loss-of-function mutations in RP genes have been reported in sporadic cancers, with the exceptions of 5q-myelodysplastic syndrome (RPS14) and microsatellite unstable CRC (RPL22), these cancers are not enriched in DBA.

Post-Transcriptional Regulation of Alpha One Antitrypsin by a Proteasome Inhibitor.

Alpha one antitrypsin (α1AT), a serine proteinase inhibitor primarily produced by the liver, protects pulmonary tissue from neutrophil elastase digestion. Mutations of the gene results in a misfolded α1AT protein which aggregates inside hepatocytes causing cellular damage. Therefore, inhibition of mutant α1AT production is one practical strategy to alleviate liver damage.

International consensus on the most useful assessments used by physical therapists to evaluate patients with temporomandibular disorders: A Delphi study.

Objective: To identify assessment tools used to evaluate patients with temporomandibular disorders (TMD) considered to be clinically most useful by a panel of international experts in TMD physical therapy (PT).

Methods: A Delphi survey method administered to a panel of international experts in TMD PT was conducted over three rounds from October 2017 to June 2018. The initial contact was made by email.

The SINEB1 element in the long non-coding RNA Malat1 is necessary for TDP-43 proteostasis.

Transposable elements (TEs) comprise a large proportion of long non-coding RNAs (lncRNAs). Here, we employed CRISPR to delete a short interspersed nuclear element (SINE) in Malat1, a cancer-associated lncRNA, to investigate its significance in cellular physiology. We show that Malat1 with a SINE deletion forms diffuse nuclear speckles and is frequently translocated to the cytoplasm.

Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome.

Down syndrome (DS) is the most common genetic cause of intellectual disability. Protein homeostasis is essential for normal brain function, but little is known about its role in DS pathophysiology. In this study, we found that the integrated stress response (ISR)-a signaling network that maintains proteostasis-was activated in the brains of DS mice and individuals with DS, reprogramming translation.

Differences between acute and chronic stress granules, and how these differences may impact function in human disease.

Stress granules are macromolecular aggregates of mRNA and proteins assembling in response to stresses that promote the repression of protein synthesis. Most of the work characterizing stress granules has been done under acute stress conditions or during viral infection. Comparatively less work has been done to understand stress granule assembly during chronic stress, specifically regarding the composition and function of stress granules in this alternative context.

Metformin blocks MYC protein synthesis in colorectal cancer via mTOR-4EBP-eIF4E and MNK1-eIF4G-eIF4E signaling.

The antidiabetic drug metformin has been associated with reduced colorectal cancer (CRC) risk and improved prognosis of CRC patients. However, the detailed mechanisms underlying such beneficial effects remain unknown. In this study, we aimed to evaluate metformin activity in CRC models and unveil the underlying molecular mechanisms.

Chronic starvation induces noncanonical pro-death stress granules.

Stress granules (SGs) assemble under stress-induced conditions that inhibit protein synthesis, including phosphorylation of eIF2α, inhibition of the RNA helicase eIF4a proteins or inactivation of mTORC1. Classically defined SGs are composed of translation initiation factors, 40S ribosomes, RNA-binding proteins and poly(A) mRNAs. As such, they represent an important compartment for storage of mRNAs and regulation of their translation.

FGFR1-Activated Translation of WNT Pathway Components with Structured 5' UTRs Is Vulnerable to Inhibition of EIF4A-Dependent Translation Initiation.

Cooperativity between WNT and FGF signaling is well documented in embryonic development and cancer progression, but the molecular mechanisms underlying this cross-talk remain elusive. In this study, we interrogated the dynamics of RNA levels, ribosome occupancy, and protein expression as a function of inducible FGF signaling in mouse mammary glands with constitutive WNT hyperactivation. Multiomics correlation analysis revealed a substantial discrepancy between RNA and ribosome occupancy levels versus protein levels.

Histone arginine demethylase JMJD6 is linked to stress granule assembly through demethylation of the stress granule-nucleating protein G3BP1.

Stress granules (SG) are membrane-less organelles that are condensates of stalled translation initiation complexes and mRNAs. SG formation is a cytoprotective response to environmental stress and results from protein interactions involving regions of low amino acid complexity and poorly defined post-translational modifications of SG components. Many RNA-binding proteins are methylated, and we previously demonstrated that the potent SG-nucleating protein G3BP1 is methylated by protein arginine methyltransferase 1 and 5 (PRMT1 and PRMT5).

Casein Kinase 2 Is Linked to Stress Granule Dynamics through Phosphorylation of the Stress Granule Nucleating Protein G3BP1.

Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. Previous work showed that G3BP1 is phosphorylated at serine 149, which regulates G3BP1 oligomerization, stress granule assembly, and RNase activity intrinsic to G3BP1.

Arginine Demethylation of G3BP1 Promotes Stress Granule Assembly.

Stress granules (SGs) are cytoplasmic condensates of stalled messenger ribonucleoprotein complexes (mRNPs) that form when eukaryotic cells encounter environmental stress. RNA-binding proteins are enriched for arginine methylation and facilitate SG assembly through interactions involving regions of low amino acid complexity. How methylation of specific RNA-binding proteins regulates RNA granule assembly has not been characterized.

Improving performance in the detection and management of cystic fibrosis-related diabetes in the Mountain West Cystic Fibrosis Consortium.

Objective: Cystic fibrosis (CF)-related diabetes (CFRD) is associated with increased morbidity and mortality. Improved detection and management may improve outcomes; however, actual practice falls short of published guidelines. We studied efforts to improve CFRD screening and management in the Mountain West CF Consortium (MWCFC).

Stress granules regulate double-stranded RNA-dependent protein kinase activation through a complex containing G3BP1 and Caprin1.

Unlabelled: Stress granules (SGs) are dynamic cytoplasmic repositories containing translationally silenced mRNAs that assemble upon cellular stress. We recently reported that the SG nucleating protein G3BP1 promotes antiviral activity and is essential in double-stranded RNA-dependent protein kinase (PKR) recruitment to stress granules, thereby driving phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). Here, we delineate the mechanism for SG-dependent PKR activation.

The stress granule protein G3BP1 recruits protein kinase R to promote multiple innate immune antiviral responses.

Unlabelled: Stress granules (SGs) are cytoplasmic storage sites containing translationally silenced mRNPs that can be released to resume translation after stress subsides. We previously showed that poliovirus 3C proteinase cleaves the SG-nucleating protein G3BP1, blocking the ability of cells to form SGs late in infection. Many other viruses also target G3BP1 and inhibit SG formation, but the reasons why these functions evolved are unclear.

SRC-2 is an essential coactivator for orchestrating metabolism and circadian rhythm.

Synchrony of the mammalian circadian clock is achieved by complex transcriptional and translational feedback loops centered on the BMAL1:CLOCK heterodimer. Modulation of circadian feedback loops is essential for maintaining rhythmicity, yet the role of transcriptional coactivators in driving BMAL1:CLOCK transcriptional networks is largely unexplored. Here, we show diurnal hepatic steroid receptor coactivator 2 (SRC-2) recruitment to the genome that extensively overlaps with the BMAL1 cistrome during the light phase, targeting genes that enrich for circadian and metabolic processes.

mRNA decapping enzyme 1a (Dcp1a)-induced translational arrest through protein kinase R (PKR) activation requires the N-terminal enabled vasodilator-stimulated protein homology 1 (EVH1) domain.

We have shown previously that poliovirus infection disrupts cytoplasmic P-bodies in infected mammalian cells. During the infectious cycle, poliovirus causes the directed cleavage of Dcp1a and Pan3, coincident with the dispersion of P-bodies. We now show that expression of Dcp1a prior to infection, surprisingly, restricts poliovirus infection.

Diversion of stress granules and P-bodies during viral infection.

RNA granules are structures within cells that impart key regulatory measures on gene expression. Two general types of RNA granules are conserved from yeast to mammals: stress granules (SGs), which contain many translation initiation factors, and processing bodies (P-bodies, PBs), which are enriched for proteins involved in RNA turnover. Because of the inverse relationship between appearance of RNA granules and persistence of translation, many viruses must subvert RNA granule function for replicative purposes.

Large G3BP-induced granules trigger eIF2α phosphorylation.

Stress granules are large messenger ribonucleoprotein (mRNP) aggregates composed of translation initiation factors and mRNAs that appear when the cell encounters various stressors. Current dogma indicates that stress granules function as inert storage depots for translationally silenced mRNPs until the cell signals for renewed translation and stress granule disassembly. We used RasGAP SH3-binding protein (G3BP) overexpression to induce stress granules and study their assembly process and signaling to the translation apparatus.

Animal virus schemes for translation dominance.

Viruses have adapted a broad range of unique mechanisms to modulate the cellular translational machinery to ensure viral translation at the expense of cellular protein synthesis. Many of these promote virus-specific translation by use of molecular tags on viral mRNA such as internal ribosome entry sites (IRES) and genome-linked viral proteins (VPg) that bind translation machinery components in unusual ways and promote RNA circularization. This review describes recent advances in understanding some of the mechanisms in which animal virus mRNAs gain an advantage over cellular transcripts, including new structural and biochemical insights into IRES function and novel proteins that function as alternate met-tRNA(i)(met) carriers in translation initiation.