Biology subjects

Isaguirre, C. N.

Publications and source records attributed to Isaguirre, C. N..

3 recordsLinked to original sources

bioRxiv2024

Dietary Restriction Enhances CD8+ T Cell Ketolysis to Limit Exhaustion and Boost Anti-Tumor Immunity

Reducing calorie intake without malnutrition limits tumor progression but the underlying mechanisms are poorly understood. Here we show that dietary restriction (DR) suppresses tumor growth by enhancing CD8+ T cell-mediated anti-tumor immunity. DR reshapes CD8+ T cell differentiation within the tumor microenvironment (TME), promoting the development of effector T cell subsets while limiting the accumulation of exhausted T (Tex) cells, and synergizes with anti-PD1 immunotherapy to restrict tumor growth. Mechanistically, DR enhances CD8+ T cell metabolic fitness through increased ketone body oxidation (ketolysis), which boosts mitochondrial membrane potential and fuels tricarboxylic acid (TCA) cycle-dependent pathways essential for T cell function. T cells deficient for ketolysis exhibit reduced mitochondrial function, increased exhaustion, and fail to control tumor growth under DR conditions. Our findings reveal a critical role for the immune system in mediating the anti-tumor effects of DR, highlighting nutritional modulation of CD8+ T cell fate in the TME as a critical determinant of anti-tumor immunity.

immunology↗

bioRxiv2024

A high-throughput screening platform for discovering bacterial species and small molecules that modify animal physiology

Canonical polyamines such as agmatine, putrescine, and spermidine are evolutionarily conserved metabolites found in nearly all forms of life ranging from bacteria to humans. Recently, interactions between polyamines produced by gut bacteria and human intestinal cells have been proposed to contribute to both Irritable Bowel Syndrome with Diarrhea (IBS-D) and inflammatory bowel diseases. However, the molecular mechanisms that underlie these effects are often unclear due in part to limitations in the methods used to manipulate and study polyamine functions in vivo. Here, we developed a Caenorhabditis elegans based screening platform and a modified LC-MS approach for profiling polyamine metabolites. We combined these methods to make the unexpected discovery that dysfunctional polyamine metabolism in both Gram-negative (E. coli) and Gram-positive (B. subtilis) bacteria can result in the accumulation of a noncanonical polyamine intermediate, N1-Aminopropylagmatine (N1-APA). We further find that N1-APA is produced via spermidine synthase (SpeE) and that it is bioactive when encountered by animals. Specifically, we find that when N1-APA is produced by bacteria in animal intestines it can be transported into intestinal cells via the polyamine transporter CATP-5 where it antagonizes both animal development and mitochondrial function across diverse animal species. Lastly, we find that N1-APA functions analogously to the deoxyhypusine synthase inhibitor GC7. For example, like GC7, N1-APA antagonizes eIF5A hypusination and inhibits the alternative activation of mammalian macrophages. To our knowledge, these findings are the first to demonstrate that N1-APA is a bioactive metabolite and that bacteria can produce a small molecule that functions similarly to existing deoxyhypusine synthase inhibitors. Furthermore, these results suggest an exciting new mechanistic hypothesis for why the loss of speB in gut microbes, including E. coli, has been both linked to inflammatory bowel disease (IBD) in humans and found to drive IBD in germ free mice.

genetics↗

bioRxiv2024

Single-embryo metabolomics reveals developmental metabolism in the early Drosophila embryo

Early embryonic development is characterized by the transition from maternal factor reliance to zygotic control. These processes set the stage for the embryos basic structure and cellular differentiation. While relatively detailed knowledge exists of the transcriptional events during early development, little is known about the concurrent metabolic processes. Understanding these processes, however, is important since they are linked to cell fate determination and organ and tissue formation. The primary reasons for the limited progress in the field are technical limitations due to the small amount of material available during early embryonic time windows. Here, we introduce a novel single-embryo methodology that places us in an exciting position to analyze the early embryos metabolome and transcriptome in an integrated manner and at high temporal resolution. The resulting data allow us to map concomitant metabolic and transcriptional programs in early Drosophila embryonic development. Our results reveal that a substantial number of metabolites exhibit dynamic patterns with some changing even before the onset of zygotic transcription. dNTPs for example show a temporal pattern that correlates with cell division patterns in the early embryo. In summary, here we present an operationally simple single-embryo metabolomics methodology and provide a detailed picture of early developmental metabolic processes at unprecedented temporal resolution.

developmental biology↗