Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity.

Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6-8. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP-PKA-CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.

The Metabolome of Associations between Xylem-Feeding Insects and their Bacterial Symbionts.

Metabolomics has increasingly led to important insights in chemical ecology by identifying environmentally relevant small molecules that mediate inter-organismal interactions. Nevertheless, the application of metabolomics to investigate interactions between phytophagous insects and their microbial symbionts remains underutilized. Here, we investigated the metabolomes of the bacteriomes (organs bearing symbiotic bacteria) isolated from natural populations of five species of xylem-feeding insects. We identified three patterns. First, the metabolomes varied among the five species, likely influenced by insect phylogeny, food plant and taxonomic identity of the symbionts. Second, the ratio of glutamine: glutamate in the bacteriomes was 0.7-3.6 to 1, indicative of nitrogen-sufficient metabolism and raising the possibility that the insect sustains nitrogen-enriched status of the bacteriomes despite the nitrogen scarcity of the xylem diet. Finally, bacteriomes from insect species bearing genetically-similar symbionts displayed limited variation in their metabolomes, suggesting that the metabolic pattern of the bacteriome metabolic pools is correlated with the genetic repertoire of the symbionts. Altogether, these metabolomic patterns yield specific hypotheses of underlying processes that are testable by wider sampling of natural populations and experimental study.

NRAS Mutant Dictates AHCYL1-Governed ER Calcium Homeostasis for Melanoma Tumor Growth.

Calcium homeostasis is critical for cell proliferation, and emerging evidence shows that cancer cells exhibit altered calcium signals to fulfill their need for proliferation. However, it remains unclear whether there are oncogene-specific calcium homeostasis regulations that can expose novel therapeutic targets. Here, from RNAi screen, we report that adenosylhomocysteinase like protein 1 (AHCYL1), a suppressor of the endoplasmic reticulum (ER) calcium channel protein inositol trisphosphate receptor (IP3R), is selectively upregulated and critical for cell proliferation and tumor growth potential of human NRAS-mutated melanoma, but not for melanoma expressing BRAF V600E. Mechanistically, AHCYL1 deficiency results in decreased ER calcium levels, activates the unfolded protein response (UPR), and triggers downstream apoptosis. In addition, we show that AHCYL1 transcription is regulated by activating transcription factor 2 (ATF2) in NRAS-mutated melanoma. Our work provides evidence for oncogene-specific calcium regulations and suggests AHCYL1 as a novel therapeutic target for RAS mutant-expressing human cancers, including melanoma. IMPLICATIONS: Our findings suggest that targeting the AHCYL1-IP3R axis presents a novel therapeutic approach for NRAS-mutated melanomas, with potential applicability to all cancers harboring RAS mutations, such as KRAS-mutated human colorectal cancers.

Cellular signals converge at the NOX2-SHP-2 axis to induce reductive carboxylation in cancer cells.

Environmental stresses, including hypoxia or detachment for anchorage independence, or attenuation of mitochondrial respiration through inhibition of electron transport chain induce reductive carboxylation in cells with an enhanced fraction of citrate arising through reductive metabolism of glutamine. This metabolic process contributes to redox homeostasis and sustains biosynthesis of lipids. Reductive carboxylation is often dependent on cytosolic isocitrate dehydrogenase 1 (IDH1). However, whether diverse cellular signals induce reductive carboxylation differentially or through a common signaling converging node remains unclear. We found that induction of reductive carboxylation commonly requires enhanced tyrosine phosphorylation and activation of IDH1, which, surprisingly, is achieved by attenuation of a cytosolic protein tyrosine phosphatase, Src homology region 2 domain-containing phosphatase-2 (SHP-2). Mechanistically, diverse signals induce reductive carboxylation by converging at upregulation of NADPH oxidase 2, leading to elevated cytosolic reactive oxygen species that consequently inhibit SHP-2. Together, our work elucidates the signaling basis underlying reductive carboxylation in cancer cells.

Syntrophic splitting of central carbon metabolism in host cells bearing functionally different symbiotic bacteria.

Insects feeding on the nutrient-poor diet of xylem plant sap generally bear two microbial symbionts that are localized to different organs (bacteriomes) and provide complementary sets of essential amino acids (EAAs). Here, we investigate the metabolic basis for the apparent paradox that xylem-feeding insects are under intense selection for metabolic efficiency but incur the cost of maintaining two symbionts for functions mediated by one symbiont in other associations. Using stable isotope analysis of central carbon metabolism and metabolic modeling, we provide evidence that the bacteriomes of the spittlebug Clastoptera proteus display high rates of aerobic glycolysis, with syntrophic splitting of glucose oxidation. Specifically, our data suggest that one bacteriome (containing the bacterium Sulcia, which synthesizes seven EAAs) predominantly processes glucose glycolytically, producing pyruvate and lactate, and the exported pyruvate and lactate is assimilated by the second bacteriome (containing the bacterium Zinderia, which synthesizes three energetically costly EAAs) and channeled through the TCA cycle for energy generation by oxidative phosphorylation. We, furthermore, calculate that this metabolic arrangement supports the high ATP demand in Zinderia bacteriomes for Zinderia-mediated synthesis of energy-intensive EAAs. We predict that metabolite cross-feeding among host cells may be widespread in animal-microbe symbioses utilizing low-nutrient diets.