Programme of self-reactive innate-like T cell-mediated cancer immunity.

Cellular transformation induces phenotypically diverse populations of tumour-infiltrating T cells, and immune checkpoint blockade therapies preferentially target T cells that recognize cancer cell neoantigens. Yet, how other classes of tumour-infiltrating T cells contribute to cancer immunosurveillance remains elusive. Here, in a survey of T cells in mouse and human malignancies, we identified a population of αβ T cell receptor (TCR)-positive FCER1G-expressing innate-like T cells with high cytotoxic potential (ILTCKs).

Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses.

Aerobic glycolysis-the Warburg effect-converts glucose to lactate via the enzyme lactate dehydrogenase A (LDHA) and is a metabolic feature of effector T cells. Cells generate ATP through various mechanisms and Warburg metabolism is comparatively an energy-inefficient glucose catabolism pathway. Here, we examined the effect of ATP generated via aerobic glycolysis in antigen-driven T cell responses.

Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity.

Infection triggers expansion and effector differentiation of T cells specific for microbial antigens in association with metabolic reprograming. We found that the glycolytic enzyme lactate dehydrogenase A (LDHA) is induced in CD8 T effector cells through phosphoinositide 3-kinase (PI3K) signaling. In turn, ablation of LDHA inhibits PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1, causing defective antimicrobial immunity.

A Tug-of-War Over Methionine.

Nutrient acquisition and metabolism are integral components of cell growth, proliferation, and differentiation programs. In a recent study in Nature, Bian et al. (2020) revealed that cancer cells outcompete T cells for methionine uptake, resulting in diminished SAM production, attenuated H3K79 dimethylation, decreased STAT5 expression, and impaired T cell immunity to cancer.

Tob2 phosphorylation regulates global mRNA turnover to reshape transcriptome and impact cell proliferation.

Tob2, an anti-proliferative protein, promotes deadenylation through recruiting Caf1 deadenylase to the mRNA poly(A) tail by simultaneously interacting with both Caf1 and poly(A)-binding protein (PABP). Previously, we found that changes in Tob2 phosphorylation can alter its PABP-binding ability and deadenylation-promoting function. However, it remained unknown regarding the relevant kinase(s).

Comprehensive Characterization of Alternative Polyadenylation in Human Cancer.

Background: Alternative polyadenylation (APA) is emerging as a major post-transcriptional mechanism for gene regulation, and dysregulation of APA contributes to several human diseases. However, the functional consequences of APA in human cancer are not fully understood. Particularly, there is no large-scale analysis in cancer cell lines.

Antagonistic actions of two human Pan3 isoforms on global mRNA turnover.

Deadenylation is a fundamental process that regulates eukaryotic gene expression. Mammalian deadenylation exhibits biphasic kinetics, with the Pan2-Pan3 and Ccr4-Caf1 deadenylase complexes mediating the first and second phase, respectively; however, the significance of the biphasic nature of deadenylation in mRNA turnover remains unclear. In this study, we discovered that two distinct isoforms of human Pan3 display opposing properties necessary for coordinating the two phases of deadenylation.

Emerging Themes in Regulation of Global mRNA Turnover in cis.

mRNA is the molecule that conveys genetic information from DNA to the translation apparatus. mRNAs in all organisms display a wide range of stability, and mechanisms have evolved to selectively and differentially regulate individual mRNA stability in response to intracellular and extracellular cues. In recent years, three seemingly distinct aspects of RNA biology-mRNA N-methyladenosine (m6A) modification, alternative 3' end processing and polyadenylation (APA), and mRNA codon usage-have been linked to mRNA turnover, and all three aspects function to regulate global mRNA stability in cis.

CFIm25 regulates glutaminase alternative terminal exon definition to modulate miR-23 function.

Alternative polyadenylation (APA) and alternative splicing (AS) provide mRNAs with the means to avoid microRNA repression through selective shortening or differential usage of 3'UTRs. The two glutaminase (GLS) mRNA isoforms, termed KGA and GAC, contain distinct 3'UTRs with the KGA isoform subject to repression by miR-23. We show that depletion of the APA regulator CFIm25 causes a strong shift to the usage of a proximal poly(A) site within the KGA 3'UTR and also alters splicing to favor exclusion of the GAC 3'UTR.

MiR-26 down-regulates TNF-α/NF-κB signalling and IL-6 expression by silencing HMGA1 and MALT1.

MiR-26 has emerged as a key tumour suppressor in various cancers. Accumulating evidence supports that miR-26 regulates inflammation and tumourigenicity largely through down-regulating IL-6 production, but the underlying mechanism remains obscure. Here, combining a transcriptome-wide approach with manipulation of cellular miR-26 levels, we showed that instead of directly targeting IL-6 mRNA for gene silencing, miR-26 diminishes IL-6 transcription activated by TNF-α through silencing NF-κB signalling related factors HMGA1 and MALT1.

The impact of educational workshops on individuals at risk for glaucoma in the Philadelphia Glaucoma Detection and Treatment Project.

Objectives: The purpose of this study was to investigate the impact of educational workshops, led by community health educators, on the level of knowledge, perceived risk of glaucoma, and rate of attendance in a subsequent glaucoma detection examination.

Methods: Participants attended an educational workshop about glaucoma and completed an 8-question pre- and post-test to assess knowledge. A paired samples t-test assessed mean differences in composite pre- and post-test scores, correct responses for each question, and perceived risk of glaucoma after the workshop.

Initial Experience With the New Ahmed Glaucoma Valve Model M4: Short-term Results.

Purpose: To evaluate the clinical outcomes of the new Ahmed glaucoma valve (AGV) model M4. The device consists of a porous polyethylene shell designed for improved tissue integration and reduced encapsulation of the plate for better intraocular pressure (IOP) control.

Methods: Medical records of patients with an AGV M4 implantation between December 1, 2012 and December 31, 2013 were reviewed.

ROCK inhibition enhances microRNA function by promoting deadenylation of targeted mRNAs via increasing PAIP2 expression.

The reduced expression levels and functional impairment of global miRNAs are related to various human diseases, including cancers. However, relatively little is known about how global miRNA function may be upregulated. Here, we report that global miRNA function can be enhanced by Rho-associated, coiled-coil-containing protein kinase (ROCK) inhibitors.

Emerging mechanisms of mRNP remodeling regulation.

The assembly and remodeling of the components of messenger ribonucleoprotein particles (mRNPs) are important in determining the fate of a messenger RNA (mRNA). A combination of biochemical and cell biology research, recently complemented by genome-wide high-throughput approaches, has led to significant progress on understanding the formation, dynamics, and function of mRNPs. These studies also advanced the challenging process of identifying the evolving constituents of individual mRNPs at various stages during an mRNA's lifetime.

CFIm25 links alternative polyadenylation to glioblastoma tumour suppression.

The global shortening of messenger RNAs through alternative polyadenylation (APA) that occurs during enhanced cellular proliferation represents an important, yet poorly understood mechanism of regulated gene expression. The 3' untranslated region (UTR) truncation of growth-promoting mRNA transcripts that relieves intrinsic microRNA- and AU-rich-element-mediated repression has been observed to correlate with cellular transformation; however, the importance to tumorigenicity of RNA 3'-end-processing factors that potentially govern APA is unknown. Here we identify CFIm25 as a broad repressor of proximal poly(A) site usage that, when depleted, increases cell proliferation.

Protein segregase meddles in remodeling of mRNA-protein complexes.

Remodeling of RNA-protein complexes (mRNPs) plays a critical role in mRNA biogenesis and metabolism. However, relatively little is known about the underlying mechanism and regulation of the mRNP remodeling. In this issue of Genes & Development, Zhou and colleagues (pp.

Phosphorylation at intrinsically disordered regions of PAM2 motif-containing proteins modulates their interactions with PABPC1 and influences mRNA fate.

Cytoplasmic poly(A)-binding protein (PABP) C1 recruits different interacting partners to regulate mRNA fate. The majority of PABP-interacting proteins contain a PAM2 motif to mediate their interactions with PABPC1. However, little is known about the regulation of these interactions or the corresponding functional consequences.

Deadenylation and P-bodies.

Deadenylation is the major step in triggering mRNA decay and results in mRNA translation inhibition in eukaryotic cells. Therefore, it is plausible that deadenylation also induces the mRNP remodeling required for formation of GW bodies or RNA processing bodies (P-bodies), which harbor translationally silenced mRNPs. In this chapter, we discuss several examples to illustrate the roles of deadenylation in regulating gene expression.