Vo, P. | bioRxiv Science

bioRxiv2024

Comamonas aquatica inhibits TIR-1/SARM1 induced axon degeneration

Emerging evidence suggests the microbiome critically influences the onset and progression of neurodegenerative diseases; however, the identity of neuroprotective bacteria and the molecular mechanisms that respond within the host remain largely unknown. We took advantage of Caenorhabditis elegans well characterized nervous system and ability to eat uni-bacterial diets to determine how metabolites and neuroprotective molecules from single species of bacteria suppress degeneration of motor neurons. We found Comamonas aquatica significantly protects against degeneration induced by overexpressing a key regulator of axon degeneration, TIR-1/SARM1. Genetic analyses and metabolomics reveal Comamonas protects against neurodegeneration by providing sufficient Vitamin B12 to activate METR-1/MTR methionine synthase in the intestine, which then lowers toxic levels of homocysteine in TIR-1-expressing animals. Defining a molecular pathway between Comamonas and neurodegeneration adds significantly to our understanding of gut-brain interactions and, given the prominent role of homocysteine in neurodegenerative disorders, reveals how such a bacterium could protect against disease.

neuroscience↗

bioRxiv2024

Structural and systems characterization of phosphorylation on metabolic enzymes identifies sex-specific metabolic reprogramming in obesity

Coordination of adaptive metabolism through cellular signaling networks and metabolic response is essential for balanced flow of energy and homeostasis. Post-translational modifications such as phosphorylation offer a rapid, efficient, and dynamic mechanism to regulate metabolic networks. Although numerous phosphorylation sites have been identified on metabolic enzymes, much remains unknown about their contribution to enzyme function and systemic metabolism. In this study, we stratify phosphorylation sites on metabolic enzymes based on their location with respect to functional and dimerization domains. Our analysis reveals that the majority of published phosphosites are on oxidoreductases, with particular enrichment of phosphotyrosine (pY) sites in proximity to binding domains for substrates, cofactors, active sites, or dimer interfaces. We identify phosphosites altered in obesity using a high fat diet (HFD) induced obesity model coupled to multiomics, and interrogate the functional impact of pY on hepatic metabolism. HFD induced dysregulation of redox homeostasis and reductive metabolism at the phosphoproteome and metabolome level in a sex-specific manner, which was reversed by supplementing with the antioxidant butylated hydroxyanisole (BHA). Partial least squares regression (PLSR) analysis identified pY sites that predict HFD or BHA induced changes of redox metabolites. We characterize predictive pY sites on glutathione S-transferase pi 1 (GSTP1), isocitrate dehydrogenase 1 (IDH1), and uridine monophosphate synthase (UMPS) using CRISPRi-rescue and stable isotope tracing. Our analysis revealed that sites on GSTP1 and UMPS inhibit enzyme activity while the pY site on IDH1 induces activity to promote reductive carboxylation. Overall, our approach provides insight into the convergence points where cellular signaling fine-tunes metabolism. Summary StatementBy employing a multi-disciplinary approach we stratify structural features of phosphorylation sites on metabolic enzymes, map the systems level changes induced by obesity, identify key pathways with sex specific phosphoproteomic responses, and validate the functional role of phosphorylation sites for select enzymes.

biochemistry↗