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bioRxiv · 10.1101/2024.04.12.589224

Soluble αβ-tubulins reversibly sequester TTC5 to regulate tubulin mRNA decay

Batiuk, A.·Höpfler, M.·Almeida, A. C.·En-Jie, D. T.·Vadas, O.·Vartholomaiou, E.·Hegde, R. S.·Lin, Z.·Gasic, I.
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Abstract

Microtubules, built from heterodimers of - and {beta}-tubulins, control cell shape, mediate intracellular transport and power cell division. The concentration of {beta}-tubulins is tightly controlled through a post-transcriptional mechanism involving selective and regulated degradation of tubulin-encoding mRNAs. Degradation is initiated by TTC5, which recognizes tubulin-synthesizing ribosomes and recruits downstream effectors to trigger mRNA deadenylation. Here, we have investigated how cells regulate TTC5 activity. Biochemical and structural proteomic approaches reveal that under normal conditions, soluble {beta}-tubulins bind to and sequester TTC5, preventing it from engaging nascent tubulins at translating ribosomes. We identify the flexible C-terminal tail of TTC5 as a molecular switch, toggling between soluble {beta}-tubulin-bound and nascent tubulin-bound states. Loss of sequestration by soluble {beta}-tubulins constitutively activates TTC5, leading to diminished tubulin mRNA levels and compromised microtubule-dependent chromosome segregation during cell division. Our findings provide a paradigm for how cells regulate the activity of a specificity factor to adapt posttranscriptional regulation of gene expression to cellular needs.

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Batiuk, A., Höpfler, M., Almeida, A. C., En-Jie, D. T., Vadas, O., Vartholomaiou, E., Hegde, R. S., Lin, Z., Gasic, I.. 2024-04-13. Soluble αβ-tubulins reversibly sequester TTC5 to regulate tubulin mRNA decay. https://doi.org/10.1101/2024.04.12.589224

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