The Tubulin Code, from Molecules to Health and Disease

Annual Review of Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 39(1), P. 331 - 361

Published: Oct. 16, 2023

Microtubules are essential dynamic polymers composed of α/β-tubulin heterodimers. They support intracellular trafficking, cell division, cellular motility, and other processes. In many species, both α-tubulin β-tubulin encoded by multiple genes with distinct expression profiles functionality. further diversified through abundant posttranslational modifications, which added removed a suite enzymes to form complex, stereotyped arrays. The genetic chemical diversity tubulin constitute code that regulates intrinsic microtubule properties is read effectors, such as molecular motors microtubule-associated proteins, provide spatial temporal specificity microtubules in cells. this review, we synthesize the rapidly expanding literature highlight limitations opportunities for field. As complex arrays underlie physiological processes, better understanding how cells employ has important implications human disease ranging from cancer neurological disorders.

Language: Английский

---

Microtubule acetylation dyshomeostasis in Parkinson’s disease

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: May 8, 2023

Abstract The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule (MT)-mediated axonal transport system. This mechanistically regulated system delivers cargos (proteins, mRNAs and organelles such as mitochondria) back forth from soma to synapse. Motor proteins like kinesins dynein regulate polarized anterograde (from synapse) retrograde synapse soma) commute of cargos, respectively. Proficient by altering stability via post-translational modifications (PTMs) α- β-tubulin heterodimers, core components constructing MTs. Occurring within lumen MTs, K40 acetylation α-tubulin acetyl transferase its subsequent deacetylation HDAC6 SIRT2 are widely scrutinized PTMs that make MTs highly flexible, which turn promotes their lifespan. movement various motor proteins, including kinesin-1 (responsible for mitochondrial commute), enhanced this PTM, dyshomeostasis MT has been observed a variety neurodegenerative conditions, Alzheimer’s disease Parkinson’s (PD). PD second most common condition closely associated with impaired dynamics deregulated tubulin levels. Although relationship between status progression pathogenesis become chicken-and-egg question, our review aims provide insights into MT-mediated mitochondria PD. enzymatic regulators along synthetic modulators have also briefly explored. Moving towards tubulin-based therapy enhances could serve disease-modifying treatment neurological conditions lack it. Graphical abstract

Language: Английский

---

Tubulin tyrosination/detyrosination regulate the affinity and sorting of intraflagellar transport trains on axonemal microtubule doublets

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 26, 2025

Abstract Cilia assembly and function rely on the bidirectional transport of components between cell body ciliary tip via Intraflagellar Transport (IFT) trains. Anterograde retrograde IFT trains travel along B- A-tubules microtubule doublets, respectively, ensuring smooth traffic flow. However, mechanism underlying this segregation remains unclear. Here, we test whether tubulin detyrosination (enriched B-tubules) tyrosination A-tubules) have a role in logistics. We report that knockout detyrosinase VashL Chlamydomonas reinhardtii causes frequent train stoppages impaired growth. By reconstituting motility de-membranated axonemes synthetic microtubules, show anterograde preferentially associate with detyrosinated tyrosinated respectively. propose tyrosination/detyrosination is crucial for spatial collision-free motion, highlighting significance code transport.

Language: Английский

---

The microtubule cytoskeleton: An old validated target for novel therapeutic drugs

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: Sept. 15, 2022

Compounds targeting microtubules are widely used in cancer therapy with a proven efficacy. However, because they also target non-cancerous cells, their administration leads to numerous adverse effects. With the advancement of knowledge on structure tubulin, regulation microtubule dynamics and deregulation pathological processes, new therapeutic strategies emerging, both for treatment other diseases, such as neuronal or even heart diseases parasite infections. In addition, better understanding mechanism action well-known drugs colchicine certain kinase inhibitors contributes development these approaches. Nowadays, chemists biologists working jointly select which cytoskeleton have improved properties. On basis few examples this review attempts depict panorama recent advances.

Language: Английский

---

Tubulin engineering by semi-synthesis reveals that polyglutamylation directs detyrosination

Nature Chemistry, Journal Year: 2023, Volume and Issue: 15(8), P. 1179 - 1187

Published: June 29, 2023

Language: Английский

---

Mechanism of ribosome-associated mRNA degradation during tubulin autoregulation

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(13), P. 2290 - 2302.e13

Published: June 8, 2023

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

Language: Английский

---

Cellular cartography: Towards an atlas of the neuronal microtubule cytoskeleton

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: March 22, 2023

Microtubules, one of the major components cytoskeleton, play a crucial role during many aspects neuronal development and function, such as polarization axon outgrowth. Consequently, microtubule cytoskeleton has been implicated in neurodevelopmental neurodegenerative disorders. The polar nature microtubules is quintessential for their allowing them to serve tracks long-distance, directed intracellular transport by kinesin dynein motors. Most these motors move exclusively towards either plus- or minus-end some have shown preference dynamic stable microtubules, those bearing particular post-translational modification decorated specific microtubule-associated protein. Thus, it becomes important consider interplay features combinatorial effects on transport, well how different types are organized cell. Here, we discuss subsets terms tubulin isotypes, modifications, proteins, stability dynamicity, orientation. We highlight techniques used study and, using information from studies, try define composition, role, organization neurons.

Language: Английский

---

Microtubule-binding protein MAP1B regulates interstitial axon branching of cortical neurons via the tubulin tyrosination cycle

The EMBO Journal, Journal Year: 2024, Volume and Issue: 43(7), P. 1214 - 1243

Published: Feb. 22, 2024

Abstract Regulation of directed axon guidance and branching during development is essential for the generation neuronal networks. However, molecular mechanisms that underlie interstitial (or collateral) in mammalian brain remain unresolved. Here, we investigate vivo using an approach precise labeling layer 2/3 callosal projection neurons (CPNs). This method allows quantitative analysis axonal morphology at high acuity also manipulation gene expression well-defined temporal windows. We find GSK3β serine/threonine kinase promotes CPNs by releasing MAP1B-mediated inhibition branching. Further, tubulin tyrosination cycle a key downstream component GSK3β/MAP1B signaling. These data suggest cell-autonomous regulation cortical neuron morphology, which can release brake on upstream posttranslational code.

Language: Английский

---

Chronic Activation of Tubulin Tyrosination Improves Heart Function

Circulation Research, Journal Year: 2024, Volume and Issue: 135(9), P. 910 - 932

Published: Sept. 16, 2024

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder caused by sarcomeric gene variants and associated with left ventricular hypertrophy diastolic dysfunction. The role of microtubule network has recently gained interest findings that detyrosination (dTyr-MT) markedly elevated in heart failure. Acute reduction dTyr-MT inhibition detyrosinase (VASH [vasohibin]/SVBP [small VASH-binding protein] complex) or activation tyrosinase (TTL [tubulin tyrosine ligase]) improved contractility reduced stiffness human failing cardiomyocytes thus posed a new perspective for HCM treatment. In this study, we tested impact chronic tubulin tyrosination an mouse model ( Mybpc3 knock-in), cardiomyocytes, SVBP-deficient engineered tissues (EHTs). METHODS: Adeno-associated virus serotype 9–mediated TTL transfer was applied neonatal wild-type rodents, 3-week-old knock-in mice, induced pluripotent stem cell–derived cardiomyocytes. RESULTS: We show (1) 6 weeks dose dependently without affecting cytosolic calcium transients cardiomyocytes; (2) 12 abundance myocardium, filling, compliance, output, stroke volume mice; (3) 10 days normalized cell area (4) overexpression activated transcription tubulins other cytoskeleton components but did not significantly proteome (5) EHTs exhibited levels, higher force, faster relaxation than TTL-deficient EHTs. RNA sequencing mass spectrometry analysis revealed distinct enrichment cardiomyocyte pathways versus CONCLUSIONS: This study provides first proof concept mice improves function holds promise targeting nonsarcomeric disease.

Language: Английский

---

Crosstalk between acetylation and the tyrosination/detyrosination cycle of α-tubulin in Alzheimer’s disease

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: Aug. 26, 2022

Microtubules (MTs) support a variety of neuronal functions, such as maintenance cell structure, transport, and synaptic plasticity. Neuronal MTs are highly heterogeneous due to several tubulin isotypes the presence multiple post-translational modifications, detyrosination acetylation. The tyrosination/detyrosination cycle is key player in MT dynamics, tyrosinated associated with more dynamic MTs, while detyrosinated linked longer lived, stable MTs. Dysfunction re-tyrosination was recently correlated Alzheimer's disease progression. implication acetylation has, however, remained controversial. Here, we demonstrate that accumulates post-mortem brain tissues from patients human neurons harboring familial APP-V717I mutation. We further show re-tyrosination, which defective disease, can control acetylated primary irrespective levels enzymes regulating acetylation, suggesting reduced dynamics impaired might contribute accumulation detected disease.

Language: Английский

---