HuR—SerpinB9 Axis Regulates Tumor T-Cell Fitness and Persistence via Post-Transcriptional Control 2267776

Functional interplay between TTP/ZFP36 and HuR/ELAVL1 in cancer: a post-transcriptional regulatory network

Post-transcriptional regulation of gene expression has emerged as a fundamental determinant of cancer initiation, progression, and therapeutic response. Among the RNA-binding proteins (RBPs) involved in mRNA turnover and translational regulation, tristetraprolin (TTP), encoded by the ZFP36 gene, and “Human antigen R” (HuR), encoded by ELAVL1, represent two functionally antagonistic regulators of AU-rich element (ARE)-containing transcripts. TTP promotes the degradation of target mRNAs through recruitment of deadenylation and decay complexes, whereas HuR generally stabilizes and enhances the translation of overlapping mRNA subsets. Because many oncogenic, inflammatory, angiogenic, and metastasis-associated transcripts contain AREs within their 3′ untranslated regions, the balance between TTP-mediated decay and HuR-mediated stabilization critically influences tumor biology. Accumulating evidence demonstrates that loss of TTP expression or activity and cytoplasmic accumulation of HuR are recurrent features across multiple cancer types, including breast, colorectal, pancreatic, gastric, liver, ovarian, and lung cancers. Importantly, several studies indicate that the reciprocal interplay between these proteins establishes a post-transcriptional rheostat controlling cancer-associated RNA regulons. This review summarizes current knowledge regarding the molecular biology of TTP and HuR, emphasizing their opposing functions in mRNA metabolism and cancer progression. We discuss mechanisms regulating their expression, localization, phosphorylation, and RNA-binding activity; analyze cancer-specific evidence; and examine models in which both proteins are co-expressed or functionally interconnected. Finally, we evaluate therapeutic strategies aimed at restoring TTP function or inhibiting HuR activity and discuss future perspectives for targeting post-transcriptional regulatory networks in oncology.

Beyond Transcription: T cell-Intrinsic IRF5 Regulates Metabolism and Post-Transcriptional Responses in Autoimmunity 2309706

T cell activation is a meticulously orchestrated process that demands changes in cellular physiology, encompassing extensive transcriptional, translational, and metabolic reprogramming. While these layers of cellular regulation are crucial for T cell differentiation and function, the precise regulatory mechanisms that functionally link them remain incompletely defined. We investigated if T cell-intrinsic IRF5 exerts control beyond transcription and integrates with metabolic pathways. T cells from WT and Irf5-/- mice were activated in vitro (anti-CD3/CD28); activation (CD25, CD69, proliferation) was assessed by flow cytometry. CD40L mRNA and protein were measured. Metabolism was characterized via targeted metabolomics and nutrient transporter expression. Single-cell flow/scRNA-seq analyzed global T cell population shifts. In vivo, EAE models (Irf5-/-, T cell conditional Irf5-/-, adoptive transfer of MOG-specific Irf5-/- T cells) were used and EAE progression scored. Mechanistic analyses included mTORC1 activity, CD40L, glutamine transporters, and inflammatory cytokines in EAE mice. IRF5 is a novel T cell-intrinsic regulator of mTORC1 signaling and glutamine metabolism. Irf5 ablation impaired CD40L protein expression despite preserved mRNA induction. Loss of Irf5 shifted T cell metabolic programs and cellular bioenergetics. Single-cell analysis showed Irf5 deletion skewed T cell populations, altering differentiation. In vivo, conditional Irf5 deletion protected against EAE. Protection was due to suppressed mTORC1 activity, reduced CD40L, dysregulated glutamine transporter, and reduced inflammatory cytokines. IRF5 integrates TCR signaling, metabolic reprogramming, and effector function. It regulates transcription and critical post-transcriptional events, influencing mTORC1 signaling, CD40L expression, and glutamine metabolism. Modulating IRF5 may offer a strategy to manipulate aberrant T cell responses and mitigate T cell-mediated autoimmune conditions. Lupus Foundation of America Gina M. Finzi Fellowship (ZB), National Institutes of health grant 1R01AR076242 (BJB), National Institutes of health grant R03TR004623 (BJB), Department of Defense (DoD) CDMRP Lupus Research Program grant W81XWH-18-1-0674 (BJB), Th Therapeutic Approaches to Autoimmunity (THER)

A distal transcribed enhancer of KRAS fine-tunes Tfh-mediated vaccine response 2308711

Enhancer RNAs (eRNAs) are noncoding transcripts from active enhancers whose functions in adaptive immunity are poorly defined. Because small changes in signaling strength can alter T cell fate and B cell help, we hypothesized that eRNAs act as rheostats for key fate decisions and signaling modules shaping antigen-induced immune responses. We integrated rRNA-depleted RNA-seq, ATAC-seq, and ChIP-seq to map transcribed enhancers in human B, CD4, and CD8 T cells. We then focused on a conserved eRNA ∼140 kb upstream of KRAS (eKRAS) and tested its function using si/shRNA, CRISPR perturbations, and phospho-signaling assays in human T cells, together with eKras—/— mice, mixed bone marrow chimeras, influenza infection, and SARS-CoV-2 mRNA vaccination with downstream cellular and serologic analyses. We catalogued and characterized ∼2,000 eRNAs in human adaptive immune cells; eKRAS was among the most highly expressed and conserved and functioned as a cis-acting enhancer of KRAS. Disruption of eKRAS reduced KRAS mRNA and attenuated RAS-ERK activation. Although eKras—/— mice developed normally, immunized mixed chimeras revealed a cell-intrinsic defect in T follicular helper (Tfh) differentiation, with impaired germinal center formation, reduced Tfh effector programs, and defective neutralizing antibody responses to protein antigens and influenza. Following SARS-CoV-2 mRNA vaccination, eKras—/— mice showed reduced class-switched anti-spike antibodies. An eKRAS-dependent Tfh transcriptional program was conserved in human blood and associated with neutralizing antibody titers after COVID-19 vaccination. We define a systematic catalog of eRNAs in human adaptive immune cells and identify a distal transcribed enhancer that fine-tunes KRAS signaling in Tfh cells to support effective vaccine responses. These findings establish eRNAs as noncoding regulators of T cell circuits controlling antibody production and nominate the eKRAS-KRAS axis as a target to optimize humoral immunity. N/A Immune Response Regulation: Molecular Mechanisms (IRM)

NTMT1 (METTL11A) promotes MYC-dependent proliferation and downstream HLA-A suppression in cervical cancer

Background Identifying upstream molecular regulators linking tumor proliferation with immune-related alterations remains an important challenge in cancer therapy. NTMT1 (METTL11A), a protein N-terminal methyltransferase, has been implicated in tumorigenesis; however, its role in coordinating tumor–immune interaction is poorly understood. Methods We performed integrative single-cell RNA sequencing (GSE208653) and spatial transcriptomics (GSE208654) analyses to characterize NTMT1 expression and function in cervical cancer. Spatial deconvolution and microenvironmental co-localization analyses were used to define context-specific effects. Functional validation was conducted using RT–qPCR, Western blotting, multiplex immunofluorescence, and flow cytometry-based assays. Results NTMT1 exhibited heterogeneous expression across epithelial and immune cell populations, with enrichment in squamous cell carcinoma. Spatial transcriptomics revealed that NTMT1-positive regions were associated with altered immune composition, including reduced macrophage and increased NK/T cell infiltration. In epithelial-enriched regions, NTMT1 expression correlated with activation of cell cycle pathways, including MYC, E2F1, CDK1, and CCNB1. Functional experiments demonstrated that NTMT1 promotes cell cycle progression via MYC upregulation. In epithelial–NK/T co-localization niches, NTMT1 was associated with modulation of antigen presentation pathways and suppression of HLA-A expression. Functionally, NTMT1 overexpression reduced IFN-γ production by CD8+ T cells under the co-culture conditions used in this study, which was partially restored by HLA-A re-expression. Conclusion NTMT1 was identified as a candidate regulator associated with MYC activation and HLA-A suppression. Although the precise molecular mechanism remains to be elucidated, functional experiments demonstrated that NTMT1 overexpression was accompanied by increased MYC expression, reduced HLA-A expression, enhanced cell-cycle progression, and impaired CD8+ T-cell function. These findings identify NTMT1 as a candidate regulatory node associated with MYC activation and downstream HLA-A suppression, warranting further mechanistic and in-vivo investigation, highlighting NTMT1 as a promising candidate for future therapeutic investigation. Further in vivo studies will be required to determine its suitability as a target for combination immunotherapy.

NRGN inhibits CD8⁺ T cell effector function by downregulating MHC-I expression through the FMR1-IRF8 axis in hepatocellular carcinoma.

BACKGROUND Neurogranin (NRGN) has been extensively studied as a neuron-enriched synaptic regulatory protein, yet its function in cancer remains largely unexplored. Immune evasion driven by defective antigen presentation and CD8⁺ T cell dysfunction is a hallmark of hepatocellular carcinoma (HCC). This study aimed to determine whether NRGN contributes to immune escape in HCC and to elucidate its underlying molecular mechanism. METHODS NRGN expression and clinical relevance were analyzed in public datasets and validated in HCC tissues. Transcriptomic and enrichment analyses assessed antigen presentation. Gain- and loss-of-function experiments were performed in human and murine HCC cells, while orthotopic and subcutaneous models with CD8⁺ T cell exhaustion, β2M knockout, and H-2Kb blockade evaluated immune dependence in vivo. RNA stability, RNA pulldown, RIP, co-immunoprecipitation, ubiquitination, and luciferase assays were conducted to define the molecular mechanisms. RESULTS NRGN was significantly upregulated in HCC and associated with advanced stage and poor survival, correlating inversely with GZMB⁺ CD8⁺ T cell infiltration. NRGN knockdown enriched MHC-I antigen presentation pathways and restored MHC-I/β2M expression, tumor cell surface antigen presentation, and CD8⁺ T cell cytotoxicity. In vivo, NRGN silencing suppressed tumor growth and prolonged survival in a CD8⁺ T cell-dependent manner, effects reversed by β2m deletion or H-2Kb blockade. Mechanistically, NRGN downregulated IRF8 by reducing its mRNA stability through FMR1 and stabilizing FMR1 protein via inhibition of MYCBP2-mediated ubiquitination, thereby sustaining suppression of antigen presentation. CONCLUSIONS NRGN suppresses antigen presentation via the FMR1-IRF8-MHC-I axis, thereby impairing CD8⁺ T cell-specific effector functions and promoting immune evasion in HCC. Modulation of the NRGN-IRF8-MHC-I axis could represent a potential strategy for improving immunotherapeutic responses.

IQGAP2 regulates phagocytic-like activity and PD-L1 expression in glioma through the JAK2/STAT3 axis