IRAK4 is an immunological checkpoint in neuropsychiatric systemic lupus erythematosus.

The search for dementia treatments, including treatments for neuropsychiatric lupus (NPSLE), has not yet uncovered useful therapeutic targets that mitigate underlying inflammation. Currently, NPSLE's limited treatment options are often accompanied by severe toxicity. Blocking toll-like receptor (TLR) and IL-1 receptor signal transduction by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4) offers a new pathway for intervention. Using a pre-clinical NPSLE model, we compare lupus-like B6.MRL-Faslpr (MRL) mice with B6.MRL-Faslpr-IRAK4 kinase-dead (MRL-IRAK4-KD) mice, which are were less prone to 'general' lupus-like symptoms. We demonstrate that lupus-prone mice with a mutation in the kinase domain of IRAK4 no longer display typical lupus hallmarks such as splenomegaly, inflammation, production of hormones, and anti-double-stranded (ds)DNA antibody. water maze behavioral testing, which measures contextual associative learning, revealed that mice without functional IRAK4 displayed a recovery in memory acquisition deficits. RNA-seq approach revealed that cytokine and hormone signaling converge on the JAK/STAT pathways in the mouse hippocampus. Ultimately, the targets identified in this work may result in broad clinical value that can fill the significant scientific and therapeutic gaps precluding development of cures for dementia.

UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling.

The cytoplasmic RIG-I-like receptors (RLRs) recognize viral RNA and initiate innate antiviral immunity. RLR signaling also triggers glycolytic reprogramming through glucose transporters (GLUTs), whose role in antiviral immunity is elusive. Here, we unveil that insulin-responsive GLUT4 inhibits RLR signaling independently of glucose uptake in adipose and muscle tissues. At steady state, GLUT4 is docked at the Golgi matrix by ubiquitin regulatory X domain 9 (UBXN9, TUG). Following RNA virus infection, GLUT4 is released and translocated to the cell surface where it spatially segregates a significant pool of cytosolic RLRs, preventing them from activating IFN-ß responses. UBXN9 deletion prompts constitutive GLUT4 trafficking, sequestration of RLRs, and attenuation of antiviral immunity, whereas GLUT4 deletion heightens RLR signaling. Notably, reduced GLUT4 expression is uniquely associated with human inflammatory myopathies characterized by hyperactive interferon responses. Overall, our results demonstrate a noncanonical UBXN9-GLUT4 axis that controls antiviral immunity via plasma membrane tethering of cytosolic RLRs.

Antigen-specific downregulation of miR-150 in CD4 T cells promotes cell survival.

MicroRNA-150 (miR-150) has been shown to play a general role in the immune system, but very little is known about its role on CD4+ T cell responses. During T cell responses against superantigen Staphylococcal Enterotoxin A, miR-150 expression was down-regulated in antigen-specific CD4+ T cells but up-regulated in CD8+ T cells. CD4+ and CD8+ T cell clonal expansion was greater in miR-150-KO mice than in WT mice, but miR-150 selectively repressed IL-2 production in CD4+ T cells. Transcriptome analysis of CD4+ T cells demonstrated that apoptosis and mTOR pathways were highly enriched in the absence of miR-150. Mechanistic studies confirmed that miR-150 promoted apoptosis specifically in antigen-specific CD4+ T cells, but not in bystander CD4+ nor in CD8+ T cells. Furthermore, inhibition of mTOR-linked mitochondrial superoxidedismutase-2 increased apoptosis in miR-150-/- antigen-specific CD4+ T. Thus, miR-150 impacts CD4+ T cell helper activity by attenuating IL-2 production along with clonal expansion, and suppresses superoxidedismutase to promote apoptosis.

Optimal CD8+ T cell effector function requires costimulation-induced RNA-binding proteins that reprogram the transcript isoform landscape.

Boosting T cell activation through costimulation directs defense against cancer and viral infections. Despite multiple studies targeting costimulation in clinical trials, the increased potency and reprogramming of T cells endowed by costimulation is poorly understood. Canonical dogma states that transcription mediates T cell activation. Here, we show that the spliceosome, controlling post-transcriptional alternative splicing and alternative polyadenylation, is the most enriched pathway in T cells after CD134/CD137 costimulation. Costimulation of CD8+ T cells significantly increases expression of 29 RNA-binding proteins while RNA-seq uncovers over 1000 differential alternative splicing and polyadenylation events. Using in vivo mouse and in vitro human models, we demonstrate that RNA-binding protein Tardbp is required for effector cytokine production, CD8+ T cell clonal expansion, and isoform regulation after costimulation. The prospect of immune response optimization through reprogramming of mRNA isoform production offered herein opens new avenues for experimentally and therapeutically tuning the activities of T cells.

Nicotinamide breaks effector CD8 T cell responses by targeting mTOR signaling.

Nicotinamide (NAM) shapes T cell responses but its precise molecular mechanism of action remains elusive. Here, we show that NAM impairs naive T cell effector transition but also effector T cells themselves. Although aerobic glycolysis is a hallmark of activated T cells, CD8+ T cells exposed to NAM displayed enhanced glycolysis, yet producing significantly less IFNγ. Mechanistically, NAM reduced mTORC1 activity independently of NAD+ metabolism, decreasing IFNγ translation and regulating T cell transcriptional factors critical to effector/memory fate. Finally, the role of NAM in a biomedically relevant model of lung injury was tested. Specifically, a NAM-supplemented diet reduced systemic IL-2, antigen-specific T cell clonal expansion, and effector function after inhalation of Staphylococcus aureus enterotoxin A. These findings identify NAM as a potential therapeutic supplement that uncouples glycolysis from effector cytokine production and may be a powerful treatment for diseases associated with T cell hyperactivation.

Mammalian Polycistronic mRNAs and Disease.

Our understanding of gene expression has come far since the 'one-gene one-polypeptide' hypothesis proposed by Beadle and Tatum. In this review, we address the gradual recognition that a growing number of polycistronic genes, originally discovered in viruses, are being identified within the mammalian genome, and that these may provide new insights into disease mechanisms and treatment. We carried out a systematic literature review identifying 13 mammalian genes for which there is evidence for polycistronic expression via translation through an internal ribosome entry site (IRES). Although the canonical mechanism of translation initiation has been studied extensively, here we highlight a process of noncanonical translation, IRES-mediated translation, that is a growing source for understanding complex inheritance, the elucidation of disease mechanisms, and the discovery of novel therapeutic targets. Identification of additional polycistronic genes may provide new insights into disease therapy and allow for new discoveries of both translational and disease mechanisms.