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

Alina Batiuk, Markus Höpfler, Ana C. Almeida, Deryn Teoh En-Jie, Oscar Vadas, Evangelia Vartholomaiou, Ramanujan S. Hegde, Zhewang Lin () and Ivana Gasic ()
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Alina Batiuk: University of Geneva
Markus Höpfler: Medical Research Council Laboratory of Molecular Biology
Ana C. Almeida: University of Geneva
Deryn Teoh En-Jie: National University of Singapore
Oscar Vadas: University of Geneva
Evangelia Vartholomaiou: University of Geneva
Ramanujan S. Hegde: Medical Research Council Laboratory of Molecular Biology
Zhewang Lin: National University of Singapore
Ivana Gasic: University of Geneva

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Microtubules, built from heterodimers of α- and β-tubulins, control cell shape, mediate intracellular transport, and power cell division. The concentration of αβ-tubulins is tightly controlled through a posttranscriptional 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 investigate how cells regulate TTC5 activity. Biochemical and structural proteomic approaches reveal that under normal conditions, soluble αβ-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 αβ-tubulin-bound and nascent tubulin-bound states. Loss of sequestration by soluble αβ-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.

Date: 2024
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DOI: 10.1038/s41467-024-54036-0

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