Biology subjects

Katsumura, S.

Publications and source records attributed to Katsumura, S..

2 recordsLinked to original sources

bioRxiv2026

CNOT6 deadenylase safeguards postnatal growth and metabolic transition via Fgf21 mRNA decay

Postnatal growth and development require precise coordination of growth and metabolism to meet the biosynthetic and energetic demands of rapidly expanding organs. Fibroblast growth factor 21 (FGF21) serves as a key endocrine regulator linking nutrient availability to systemic growth control in early life and metabolic homeostasis in adulthood. Here, we identify the CCR4-NOT deadenylase complex subunit CNOT6, but not its paralog CNOT6L, as an essential post-transcriptional regulator of neonatal growth and metabolism. Loss of Cnot6 results in severe growth retardation, multi-organ hypoplasia, and increased perinatal mortality. Surviving Cnot6 knockout mice display markedly reduced body and organ size that gradually normalizes by adulthood, indicating developmental compensation. Mechanistically, Cnot6 deficiency elevates hepatic Fgf21 mRNA expression, suppresses the IGF1-IGFBP1 axis, and reprograms liver transcriptional networks controlling lipid and glucose metabolism and apoptosis. These changes are accompanied by increased ketone body production, suggesting enhanced fatty acid oxidation. Together, our findings uncover a previously unrecognized role of CNOT6 in limiting FGF21 expression to preserve anabolic metabolism during the neonatal period. This work establishes the CNOT6-FGF21 axis as a molecular checkpoint that couples mRNA decay with hormonal and metabolic coordination required for healthy postnatal growth.

molecular biology↗

bioRxiv2024

Pathogenic tau induces an adaptive elevation in mRNA translation rate at early stages of disease

Alterations in the rate and accuracy of messenger RNA (mRNA) translation are associated with aging and several neurodegenerative disorders, including Alzheimers disease and related tauopathies. We previously reported that error-containing RNA that are normally cleared via nonsense-mediated mRNA decay (NMD), a key RNA surveillance mechanism, are translated in the adult brain of a Drosophila model of tauopathy. In the current study, we find that newly-synthesized peptides and translation machinery accumulate within nuclear envelope invaginations that occur as a consequence of tau pathology, and that the rate of mRNA translation is globally elevated in early stages of disease in adult brains of Drosophila models of tauopathy. Polysome profiling from adult heads of tau transgenic Drosophila reveals the preferential translation of specific mRNA that have been previously linked to neurodegeneration. Unexpectedly, we find that panneuronal elevation of NMD further elevates the global translation rate in tau transgenic Drosophila, as does treatment with rapamycin. As NMD activation and rapamycin both suppress tau-induced neurodegeneration, their shared effect on translation suggests that elevated rates of mRNA translation are an early adaptive mechanism to limit neurodegeneration. Our work provides compelling evidence that tau-induced deficits in NMD reshape the tau translatome by increasing translation of RNA that are normally repressed in healthy cells.

neuroscience↗