The α-tubulin acetyltransferase ATAT1: structure, cellular functions, and its emerging role in human diseases

Iuzzolino, Angela; Pellegrini, Francesca Romana; Rotili, Dante; Degrassi, Francesca; Trisciuoglio, Daniela

doi:10.1007/s00018-024-05227-x

Cited by 3 publications

(1 citation statement)

References 119 publications

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“…0N3R-Tau interacted with MAP4, which is structurally similar to Tau and controls microtubule branching in neurons (Nishida et al, 2023; Tokuraku et al, 2010). 0N4R-Tau showed association with ATAT1, the enzyme responsible for acetylation of stable microtubules (Iuzzolino et al, 2024; Li & Yang, 2015). This could suggest that 0N4R-Tau promotes microtubules stability while 0N3R-Tau rather enhances plasticity, in line with the previous claim of labile plasticity being the key benefit of Tau-microtubule binding (Qiang et al, 2018) Overexpression of individual isoforms in SH-SY5Y cells did not result in changed microtubule stability or growth (Bachmann, Bell, et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Axonal Tau sorting depends on the PRR2 domain and 0N4R-specific interactions hint at distinct roles of Tau isoforms in synaptic plasticity

Bell-Simons,

Buchholz,

Klimek

et al. 2024

Preprint

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Tau pathology is a major hallmark of Alzheimer’s disease (AD) and related diseases, called tauopathies. While Tau is normally enriched in axons, somatodendritic missorting of the microtubule-associated protein is a key event in early disease development. Tau missorting promotes synaptic loss and neuronal dysfunction but the mechanisms underlying both normal axonal sorting and pathological missorting remain unclear. Interestingly, the disease-associated Tau brain isoforms show different axodendritic distribution, but the distinct role of these isoforms in health and disease largely unknown. Here, we aimed to identify domains or motifs of Tau and cellular binding partners that are required for efficient axonal Tau sorting, and we studied the differences of the isoform-specific Tau interactome. By using humanMAPT-KO induced pluripotent stem cell (iPSC)-derived glutamatergic neurons, we analyzed the sorting behavior of more than 20 truncated or phosphorylation-mutant Tau constructs, and we used TurboID-based proximity labelling and proteomics to identify sorting- and isoform-specific Tau interactors. We found that efficient axonal Tau sorting was independent of the N-terminal tail, the C-terminal repeat domains, and the general microtubule affinity of Tau. In contrast, the presence of the proline-rich region 2 (PRR2) was necessary for successful sorting. Our interactome data revealed peroxisomal accumulation of the Tau N-terminal half, while axonal Tau interacted with the PP2A activator HSP110. When we compared the interactome of 0N3R- and 0N4R-Tau, we observed specific interactions of 0N4R-Tau with regulators of presynaptic exocytosis and postsynaptic plasticity, which are partially associated with AD pathogenesis, such as members of the CDC42 pathway and the RAB11 proteins, while 0N3R-Tau bound to MAP4 and other cytoskeletal elements. In sum, our study postulates that axonal Tau sorting relies on the PRR2 domain but not on microtubule affinity, and unravels a potential isoform-specific role in synaptic function and AD-related dysfunction.

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Section: Discussionmentioning

confidence: 99%

Axonal Tau sorting depends on the PRR2 domain and 0N4R-specific interactions hint at distinct roles of Tau isoforms in synaptic plasticity

Bell-Simons,

Buchholz,

Klimek

et al. 2024

Preprint

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Neurotoxic Methamphetamine Doses Alter CDCel-1 Levels and Its Interaction with Vesicular Monoamine Transporter-2 in Rat Striatum

Chauhan,

Carruthers,

Stemmer

et al. 2024

Preprint

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In recent years, methamphetamine METH misuse in the US has been rapidly increasing and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). In addition to being dependent on the drug, people with MUD develop a variety of neurological problems related to the toxicity of this drug. A variety of molecular mechanisms underlying METH neurotoxicity has been identified, including dysfunction of the neuroprotective protein parkin. However, it is not known whether parkin loss of function within striatal dopaminergic (DAergic) terminals translates into a decrease in DA storage capacity. This study examined the relationship between parkin, its substrate cell division cycle related-1 (CDCrel-1), and vesicular monoamine transporter-2 (VMAT2) in METH neurotoxicity in male Sprague Dawley rats. To also assess individual differences in response to METH’s neurotoxic effects, a large group of rats was treated with binge METH or saline and sacrificed 1h or 24h later. This study is the first to show that binge METH alters the levels and subcellular localization of CDCrel-1 and that CDCrel-1 interacts with VMAT2 and increases its levels at the plasma membrane. Furthermore, we found wide individual differences in the responses of measured indices to METH. Proteomic analysis of VMAT-2-associated proteins revealed upregulation of several proteins involved in the exocytosis/endocytosis cycle. The results suggest that at 1h after METH binge, DAergic neurons are engaged in counteracting METH-induced toxic effects, including oxidative stress- and hyperthermia-induced inhibition of synaptic vesicle cycling, with the responses varying between individual rats. Studying CDCrel-1, VMAT2, and other proteins in large groups of outbred rats can help define individual genetic and molecular differences in responses to METH neurotoxicity which, in turn, will aid treating humans suffering from METH use disorder and its neurological consequences.

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SUMOylation of nuclear receptor Nor1/NR4A3 coordinates microtubule cytoskeletal dynamics and stability in neuronal cells

Gagnon,

Caron,

Tremblay

2024

Cell Biosci

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Background Nor1/NR4A3 is a member of the NR4A subfamily of nuclear receptors that play essential roles in regulating gene expression related to development, cell homeostasis and neurological functions. However, Nor1 is still considered an orphan receptor, as its natural ligand remains unclear for mediating transcriptional activation. Yet other activation signals may modulate Nor1 activity, although their precise role in the development and maintenance of the nervous system remains elusive. Methods We used transcriptional reporter assays, gene expression profiling, protein turnover measurement, and cell growth assays to assess the functional relevance of Nor1 and SUMO-defective variants in neuronal cells. SUMO1 and SUMO2 conjugation to Nor1 were assessed by immunoprecipitation. Tubulin stability was determined by acetylation and polymerization assays, and live-cell fluorescent microscopy. Results Here, we demonstrate that Nor1 undergoes SUMO1 conjugation at Lys-89 within a canonical ψKxE SUMOylation motif, contributing to the complex pattern of Nor1 SUMOylation, which also includes Lys-137. Disruption of Lys-89, thereby preventing SUMO1 conjugation, led to reduced Nor1 transcriptional competence and protein stability, as well as the downregulation of genes involved in cell growth and metabolism, such as ENO3, EN1, and CFLAR, and in microtubule cytoskeleton dynamics, including MAP2 and MAPT, which resulted in reduced survival of neuronal cells. Interestingly, Lys-89 SUMOylation was potentiated in response to nocodazole, a microtubule depolymerizing drug, although this was insufficient to rescue cells from microtubule disruption despite enhanced Nor1 gene expression. Instead, Lys-89 deSUMOylation reduced the expression of microtubule-severing genes like KATNA1, SPAST, and FIGN, and enhanced α-tubulin cellular levels, acetylation, and microfilament organization, promoting microtubule stability and resistance to nocodazole. These effects contrasted with Lys-137 SUMOylation, suggesting distinct regulatory mechanisms based on specific Nor1 input SUMOylation signals. Conclusions Our study provides novel insights into Nor1 transcriptional signaling competence and identifies a hierarchical mechanism whereby selective Nor1 SUMOylation may govern neuronal cytoskeleton network dynamics and resistance against microtubule disturbances, a condition strongly associated with neurodegenerative diseases.

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The α-tubulin acetyltransferase ATAT1: structure, cellular functions, and its emerging role in human diseases

Cited by 3 publications

References 119 publications

Axonal Tau sorting depends on the PRR2 domain and 0N4R-specific interactions hint at distinct roles of Tau isoforms in synaptic plasticity

Axonal Tau sorting depends on the PRR2 domain and 0N4R-specific interactions hint at distinct roles of Tau isoforms in synaptic plasticity

Neurotoxic Methamphetamine Doses Alter CDCel-1 Levels and Its Interaction with Vesicular Monoamine Transporter-2 in Rat Striatum

SUMOylation of nuclear receptor Nor1/NR4A3 coordinates microtubule cytoskeletal dynamics and stability in neuronal cells

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