Biology subjects

Gasic, I.

Publications and source records attributed to Gasic, I..

5 recordsLinked to original sources

bioRxiv2026

Tubulin autoregulation controls the biosynthesis of γ-tubulin to ensure mitotic fidelity

Microtubule organization relies on the precise control of tubulin abundance to ensure accurate cytoskeletal function and faithful cell division. While - and {beta}-tubulin levels are controlled by a well-characterized autoregulatory pathway that triggers co-translational mRNA decay in response to excess soluble tubulin, how cells regulate the abundance of the core microtubule nucleator {gamma}-tubulin has remained unclear. Here, we show that {gamma}-tubulin is regulated by the canonical tubulin autoregulatory machinery. We find that {gamma}-tubulin-encoding mRNAs are downregulated in response to elevated soluble {beta}-tubulin levels. This regulation requires TTC5 to co-translationally recognize a conserved amino-terminal MPREI motif in nascent {gamma}-tubulin proteins, and further recruit SCAPER and CCR4-NOT complex, targeting {gamma}-tubulin mRNAs for decay. Disruption of this regulatory mechanism elevates {gamma}-tubulin protein levels, increases centrosomal microtubule nucleation output, and compromises mitotic fidelity. Together, our findings establish {gamma}-tubulin as a previously unrecognized substrate of tubulin autoregulation and reveal coordinated control of tubulin biosynthesis as a key mechanism for tuning microtubule nucleation and ensuring accurate chromosome segregation.

cell biology↗

bioRxiv2025

Tubulin autoregulation tunes microtubule dynamics to support multicellular architecture and viability

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 {beta}-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, inducing microtubule hyperstability, 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.

cell biology↗

bioRxiv2024

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

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.

cell biology↗

bioRxiv2023

Mechanism of ribosome-associated mRNA degradation during tubulin autoregulation

SUMMARYMicrotubules play crucial roles in cellular architecture, intracellular transport, and mitosis. The availability of free tubulin subunits impacts polymerization dynamics and microtubule function. When cells sense excess free tubulin, they trigger degradation of the encoding mRNAs, which requires recognition of the nascent polypeptide by the tubulin-specific ribosome-binding factor TTC5. How TTC5 initiates decay of tubulin mRNAs is unknown. Here, our biochemical and structural analysis reveals that TTC5 recruits the poorly studied protein SCAPER to the ribosome. SCAPER in turn engages the CCR4-NOT deadenylase complex through its CNOT11 subunit to trigger tubulin mRNA decay. SCAPER mutants that cause intellectual disability and retinitis pigmentosa in humans are impaired in CCR4-NOT recruitment, tubulin mRNA degradation, and microtubule-dependent chromosome segregation. Our findings demonstrate how recognition of a nascent polypeptide on the ribosome is physically linked to mRNA decay factors via a relay of protein-protein interactions, providing a paradigm for specificity in cytoplasmic gene regulation.

molecular biology↗

bioRxiv2019

Tubulin mRNA stability is sensitive to change in microtubule dynamics caused by multiple physiological and toxic cues

The localization, mass, and dynamics of microtubules are important in many processes. Cells may actively monitor the state of their microtubules and respond to perturbation, but how this occurs outside mitosis is poorly understood. We used gene expression analysis in quiescent cells to analyze responses to subtle and strong perturbation of microtubules. Genes encoding -, {beta}, and {gamma}-tubulins, but not {delta}- or {varepsilon}-tubulins, exhibited the strongest differential expression response to microtubule-stabilizing versus destabilizing drugs. Q-PCR of exon versus intron sequences confirmed that these changes were caused by regulation of tubulin mRNA stability and not transcription. Using tubulin mRNA stability as a signature to query the GEO database, we find that tubulin genes respond to toxins known to damage microtubules. Importantly, we find many other experimental perturbations, including multiple signaling and metabolic inputs that trigger tubulin differential expression, suggesting their novel role in the regulation of microtubule cytoskeleton. Mechanistic follow up confirms that one important physiological signal, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) activity, indeed regulates tubulin mRNA stability via changes in microtubule dynamics. We propose that that tubulin gene expression is regulated as part of many coordinated biological responses, with wide implications in physiology and toxicology. Furthermore, we present a new way to discover microtubule regulation using genomics.

cell biology↗