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

Article Article scientifique Article Soluble αβ-tubulins reversibly sequester TTC5 to regulate tubulin mRNA decay eng 2024-11-17 author Batiuk Alina 0009-0001-5548-2057 Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland. 975251 Département de biologie moléculaire et cellulaire (MOCEL) author Höpfler Markus 0000-0002-2129-2220 Medical Research Council Laboratory of Molecular Biology, Cambridge, UK. author Coelho de Almeida Ana Isabel 0000-0002-0756-0903 Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland. 402378 Département de biologie moléculaire et cellulaire (MOCEL) author Teoh En-Jie Deryn 0000-0001-8171-5574 Department of Biological Sciences, National University of Singapore, Singapore, Singapore. author Vadas Oscar 0000-0003-3511-6479 Proteins, Peptides and RNA to Protein Core Facility, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 508966 Département de microbiologie et médecine moléculaire (MIMOL) author Vartholomaiou Evangelia 0000-0002-8664-9999 Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland. 752879 Département de biologie moléculaire et cellulaire (MOCEL) author Hegde Ramanujan S 0000-0001-8338-852X Medical Research Council Laboratory of Molecular Biology, Cambridge, UK. author Lin Zhewang 0000-0003-1301-6661 Department of Biological Sciences, National University of Singapore, Singapore, Singapore. zlin@nus.edu.sg. author Gasic Ivana 0000-0002-4824-8174 Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland. ivana.gasic@unige.ch. 796323 Département de biologie moléculaire et cellulaire (MOCEL) 9963 10.1038/s41467-024-54036-0 39551769 2041-1723 PMC11570694 https://www.nature.com/articles/s41467-024-54036-0 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. Chromosome Segregation Humans Microtubule-Associated Proteins / genetics Microtubule-Associated Proteins / metabolism Microtubules / metabolism Protein Binding RNA Stability RNA, Messenger / genetics RNA, Messenger / metabolism Ribosomes / metabolism Tubulin / genetics Tubulin / metabolism Dewey 616 Dewey 570 Damon Runyon Cancer Research Foundation DRG:227916 European Molecular Biology Organization ALTF 116-2020 RCUK | Medical Research Council MC_UP_A022_1007 National University of Singapore PYP Start-up grant European Molecular Biology Organization (EMBO) ALTF 258-2023 Swiss National Science Foundation Tubulin Quantity Control and Microtubule Homeostasis 194312 CH European Commission Understanding molecular principles of regulated mRNA degradation on translating ribosomes 101029853 mRNA-DEG-RIBOSOME EU H2020 54 Département de microbiologie et médecine moléculaire 21B 7daed2ee-1311-4824-9df9-2e51260a966a Département de biologie moléculaire et cellulaire 16484 false 1359 Groupe Gasic 443 Biologie d'un parasite intracellulaire obligatoire 773 https://www.ebi.ac.uk/pride/archive/projects/PXD050483 https://www.ebi.ac.uk/pride/archive/projects/PXD050557 Nature communications 15 1 012efd11-91fa-46a0-944f-873a7fa8f202 Article (Published version) Public Article_scientifique_from_crossref.pdf 11958511 application/pdf CC BY-4.0 0c2ae7e0f4648a9381c47a6b7b1bd599936a45fff9907da280f940f6d7c00845 b6882985-bb27-4c5c-9e4a-7558defbd89e Supplemental data Public 41467_2024_54036_MOESM1_ESM.pdf 4844542 application/pdf 6108ce87b2e5c221dd47fe5a655425e3242164a0d9f6f7502673e4a900eac6ea 225b46e7-39e5-4dac-b493-d0dae38a41e8 Supplemental data Public 41467_2024_54036_MOESM3_ESM.pdf 52896 application/pdf 8863cb3cd888f79c78ae8b4038702dbdcb36de416637d84a5f91d20342c672cd 72eef8d0-650b-446b-960f-95cc23e381c9 Supplemental data Public 41467_2024_54036_MOESM4_ESM.xlsx 170281 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 76ec460b243b5dd21ee064dba3123f69b66adc6273fb28bb5227b2d57a2fdd71 2ac385c9-146c-4a62-975b-8584bb61a454 Supplemental data Public 41467_2024_54036_MOESM5_ESM.xlsx 47877 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 178f3958c83718ad5180cd30c0f146150a3e2f746d16bc21651ac625f213ac04 1f5ba23a-a7f8-4a02-a7a2-222a073fccb6 Supplemental data Public 41467_2024_54036_MOESM6_ESM.xlsx 643813 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 2823e30d92acfe4530691260079aee0f64df8fdb510583665ae38d07eb70b762 79def45d-b633-4dc0-b705-9df1ca92edea Supplemental data Public 41467_2024_54036_MOESM8_ESM.xlsx 17147449 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 1eabe45d07a6fb69a6c52088b51a0b09a779dd265415cfb59480fdc77ccbc3f2 openAccess Faculté de médecine / Section de médecine fondamentale / Département de microbiologie et médecine moléculaire Faculté des sciences / Section de biologie / Département de biologie moléculaire et cellulaire

Title	Published in	Year	Views	Downloads

Tubulin Autoregulation: from Sensing Protein Level to mRNA Decay		2026	13	5
Soluble αβ-tubulins reversibly sequester TTC5 to regulate tubulin mRNA decay	Nature communications	2024	3	19

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