ATP-citrate lyase promotes axonal transport across species

Aviel Even; Giovanni Morelli; Silvia Turchetto; Michal Shilian; Romain Le Bail; Sophie Laguesse; Nathalie Krusy; Ariel Brisker; Alexander Brandis; Shani Inbar; Alain Chariot; Frédéric Saudou; Paula Dietrich; Ioannis Dragatsis; Bert Brone; Loïc Broix; Jean Michel Rigo; Miguel Weil; Laurent Nguyen

doi:10.1038/s41467-021-25786-y

ATP-citrate lyase promotes axonal transport across species

Aviel Even, Giovanni Morelli, Silvia Turchetto, Michal Shilian, Romain Le Bail, Sophie Laguesse, Nathalie Krusy, Ariel Brisker, Alexander Brandis, Shani Inbar, Alain Chariot, Frédéric Saudou, Paula Dietrich, Ioannis Dragatsis, Bert Brone, Loïc Broix, Jean Michel Rigo, Miguel Weil^*, Laurent Nguyen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

Microtubule (MT)-based transport is an evolutionary conserved process finely tuned by posttranslational modifications. Among them, α-tubulin acetylation, primarily catalyzed by a vesicular pool of α-tubulin N-acetyltransferase 1 (Atat1), promotes the recruitment and processivity of molecular motors along MT tracks. However, the mechanism that controls Atat1 activity remains poorly understood. Here, we show that ATP-citrate lyase (Acly) is enriched in vesicles and provide Acetyl-Coenzyme-A (Acetyl-CoA) to Atat1. In addition, we showed that Acly expression is reduced upon loss of Elongator activity, further connecting Elongator to Atat1 in a pathway regulating α-tubulin acetylation and MT-dependent transport in projection neurons, across species. Remarkably, comparable defects occur in fibroblasts from Familial Dysautonomia (FD) patients bearing an autosomal recessive mutation in the gene coding for the Elongator subunit ELP1. Our data may thus shine light on the pathophysiological mechanisms underlying FD.

Original language	English
Article number	5878
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25786-y
State	Published - 1 Dec 2021

Funding

Funders	Funder number
F.R.S.-F.N.R.S.
Fondation Médicale Reine Elisabeth
Fondation Simone et Pierre Clerdent
IAP-VII network P7/20
NeuroTalk
European Molecular Biology Organization	ASTF 174-2016
Agence Nationale de la Recherche	ANR-18-CE16-0009-01 AXYON, ANR-15-IDEX-02 NeuroCoG
Fonds De La Recherche Scientifique - FNRS	EOS 0019118F-RG36
Belgian Federal Science Policy Office
Fondation pour la Recherche Médicale	DEI20151234418
Israel Science Foundation	1688/16
Fonds Léon Fredericq

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Even, A., Morelli, G., Turchetto, S., Shilian, M., Bail, R. L., Laguesse, S., Krusy, N., Brisker, A., Brandis, A., Inbar, S., Chariot, A., Saudou, F., Dietrich, P., Dragatsis, I., Brone, B., Broix, L., Rigo, J. M., Weil, M., & Nguyen, L. (2021). ATP-citrate lyase promotes axonal transport across species. Nature Communications, 12(1), Article 5878. https://doi.org/10.1038/s41467-021-25786-y

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title = "ATP-citrate lyase promotes axonal transport across species",

abstract = "Microtubule (MT)-based transport is an evolutionary conserved process finely tuned by posttranslational modifications. Among them, α-tubulin acetylation, primarily catalyzed by a vesicular pool of α-tubulin N-acetyltransferase 1 (Atat1), promotes the recruitment and processivity of molecular motors along MT tracks. However, the mechanism that controls Atat1 activity remains poorly understood. Here, we show that ATP-citrate lyase (Acly) is enriched in vesicles and provide Acetyl-Coenzyme-A (Acetyl-CoA) to Atat1. In addition, we showed that Acly expression is reduced upon loss of Elongator activity, further connecting Elongator to Atat1 in a pathway regulating α-tubulin acetylation and MT-dependent transport in projection neurons, across species. Remarkably, comparable defects occur in fibroblasts from Familial Dysautonomia (FD) patients bearing an autosomal recessive mutation in the gene coding for the Elongator subunit ELP1. Our data may thus shine light on the pathophysiological mechanisms underlying FD.",

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AU - Even, Aviel

AU - Morelli, Giovanni

AU - Turchetto, Silvia

AU - Shilian, Michal

AU - Bail, Romain Le

AU - Laguesse, Sophie

AU - Krusy, Nathalie

AU - Brisker, Ariel

AU - Brandis, Alexander

AU - Inbar, Shani

AU - Chariot, Alain

AU - Saudou, Frédéric

AU - Dietrich, Paula

AU - Dragatsis, Ioannis

AU - Brone, Bert

AU - Broix, Loïc

AU - Rigo, Jean Michel

AU - Weil, Miguel

AU - Nguyen, Laurent

PY - 2021/12/1

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N2 - Microtubule (MT)-based transport is an evolutionary conserved process finely tuned by posttranslational modifications. Among them, α-tubulin acetylation, primarily catalyzed by a vesicular pool of α-tubulin N-acetyltransferase 1 (Atat1), promotes the recruitment and processivity of molecular motors along MT tracks. However, the mechanism that controls Atat1 activity remains poorly understood. Here, we show that ATP-citrate lyase (Acly) is enriched in vesicles and provide Acetyl-Coenzyme-A (Acetyl-CoA) to Atat1. In addition, we showed that Acly expression is reduced upon loss of Elongator activity, further connecting Elongator to Atat1 in a pathway regulating α-tubulin acetylation and MT-dependent transport in projection neurons, across species. Remarkably, comparable defects occur in fibroblasts from Familial Dysautonomia (FD) patients bearing an autosomal recessive mutation in the gene coding for the Elongator subunit ELP1. Our data may thus shine light on the pathophysiological mechanisms underlying FD.

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ATP-citrate lyase promotes axonal transport across species

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