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Tubulin autoregulation tunes microtubule dynamics to support multicellular architecture and viability

ABSTRACT: Abstract Alpha- and beta-tubulin heterodimers dynamically assemble into microtubules, key cytoskeletal elements involved in intracellular trafficking, cell adhesion, and division. The availability of free tubulins regulates the synthesis of new subunits. In response to excessive soluble αβ-tubulins, tetratricopeptide protein 5 (TTC5) selectively recognizes nascent tubulins at the ribosome, recruiting downstream effectors that degrade their encoding messenger RNAs, in a process known as tubulin autoregulation. Despite its well-characterized molecular framework, the biological relevance of this regulatory pathway remains unknown. Here, using human 3D cellular models, advanced optics, and genetic perturbation of tubulin biosynthesis, we reveal that loss of TTC5-dependent tubulin autoregulation elevates soluble tubulin levels, increasing microtubule stability and disrupting cytoskeletal organization. These defects impair the localization of adhesion molecules at cell-cell junctions and extracellular matrix interfaces, compromising tissue architecture and reducing overall cell viability. Our findings establish tubulin autoregulation as a critical mechanism that tunes microtubule dynamics to sustain cellular integrity and tissue homeostasis. Note: quantitative mass spectrometry was used to determine the relative abundance of alpha- and beta-tubulin isotypes, as well as, adhesion proteins in TTC5 KO versus parental spheroids.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, Cell Culture, Hela Cell

SUBMITTER: Ana Coelho Almeida

LAB HEAD: Ivana Gasic

PROVIDER: PXD076805 | Pride | 2026-06-17

REPOSITORIES: Pride

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			Action	DRS
	231211_IGasic_004_00751_PAR_1_SW_600ng.raw	Raw
	231211_IGasic_004_00752_PAR_2_SW_600ng.raw	Raw
	231211_IGasic_004_00753_PAR_3_SW_600ng.raw	Raw
	231211_IGasic_004_00754_KO_1_SW_600ng.raw	Raw
	231211_IGasic_004_00755_KO_2_SW_600ng.raw	Raw

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Project description:Background. Most methods for constructing aneuploid yeast strains that have gained a specific chromosome rely on spontaneous failures of cell division fidelity. In Saccharomyces cerevisiae, extra chromosomes can be obtained when errors in meiosis or mitosis lead to nondisjunction, or when nuclear breakdown occurs in heterokaryons. We describe a strategy for constructing N+1 disomes that does not require such spontaneous failures. The method combines two well-characterized genetic tools: a conditional centromere that transiently blocks disjunction of one specific chromosome, and a duplication marker assay that identifies disomes among daughter cells. To test the strategy, we targeted chromosomes III, IV, and VI for duplication. Results. The centromere of each target chromosome was replaced by a conditional centromere that can be blocked by growth in galactose, and ura3::HIS3, a duplication marker. Transient exposure to galactose induced the appearance of colonies carrying duplicated markers for chromosomes III or IV, but not VI. Microarray-based comparative genomic hybridization (CGH) confirmed that disomic strains carrying extra chromosome III or IV were generated. Chromosome VI contains several genes known to be deleterious when overexpressed, including the beta-tubulin gene TUB2. To test whether a tubulin stoichiometry imbalance prevents viability in cells carrying an extra chromosome VI, we supplied the parent strain with extra copies of the alpha-tubulin gene TUB1, then induced nondisjunction. Galactose-dependent chromosome VI disomes were produced, as revealed by CGH. Some chromosome VI disomes also carried extra, unselected copies of additional chromosomes. Conclusions. This method causes efficient nondisjunction of a targeted chromosome and allows resulting disomic cells to be identified and maintained. We used the method to test the role of tubulin imbalance in the apparent lethality of disomic chromosome VI. Our results indicate that a tubulin imbalance is necessary for disomic VI lethality, but it may not be the only dosage-dependent effect. Keywords: comparative genomic hybridization, CGH Candidate disomes (Ura+His+) were compared to their euploid parents by CGH. 27 candidate strains were examined with 27 arrays. 4 candidates targeted chromosome III (3 induced, 1 spontaneous), 14 candidates targeted chromosome IV (8 induced, 6 spontaneous), and 9 candidates targeted chromosome VI (all induced).

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Tubulin autoregulation tunes microtubule dynamics to support multicellular architecture and viability

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