CLASP Mediates Microtubule Repair by Restricting Lattice Damage and Regulating Tubulin Incorporation

Aher, Amol; Rai, Dipti; Schaedel, Laura; Gaillard, Jérémie; John, Karin; Liu, Qingyang; Altelaar, Maarten; Blanchoin, Laurent; Théry, Manuel; Akhmanova, Anna

doi:10.1016/j.cub.2020.03.070

Cited by 65 publications

(71 citation statements)

References 35 publications

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“…These damage sites get repaired by incorporating GTP-tubulin. Some proteins have recently been reported to cause tubulin dissociation from the shaft or to mediate GTP-tubulin incorporation (Vemu et al, 2018; Triclin et al, 2018; Aher et al, 2020;). At a GTP-tubulin incorporation site, depolymerizing microtubules can be rescued and start re-growing.…”

Section: Introductionmentioning

confidence: 99%

Motor usage imprints microtubule stability in the shaft

Andreu-Carbó

Fernandes

Velluz

et al. 2021

Preprint

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Tubulin dimers assemble into dynamic microtubules which are used by molecular motors as tracks for intracellular transport. Organization and dynamics of the microtubule network is commonly thought to be regulated at the polymer ends, where tubulin-dimers can be added or removed. Here we show that molecular motors running on microtubules cause exchange of dimers along the shaft. These sites of dimer exchange act as rescue sites where depolymerising microtubules stop shrinking and start re-growing. Consequently, the average length of microtubules increases depending on how frequently they are used as motor tracks. An increase of motor activity densifies the cellular microtubule network and enhances cell polarity. Running motors leave marks in the shaft serving as traces of microtubule usage to organize the polarity landscape of the cell.

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Section: Introductionmentioning

confidence: 99%

Motor usage imprints microtubule stability in the shaft

Andreu-Carbó

Fernandes

Velluz

et al. 2021

Preprint

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“…In vitro, MTs undergo polymerisation in the absence of enzymatic catalysis, but the addition of factors such as CLASPs, stathmins, tau, Eb proteins or XMAP215 can enhance and refine the process (Aher, Rai et al, 2020, Al-Bassam, Kim et al, 2010, Brouhard, Stear et al, 2008, Drechsel, Hyman et al, 1992, Li, Moriwaki et al, 2012, Manna, Thrower et al, 2009, Zanic, Widlund et al, 2013. Accordingly, many candidate regulators have been proposed in the literature to regulate MT polymerisation in axons, comprising factors that are MT plus endassociating, MT shaft-binding or involved in tubulin provision (summarised in (Voelzmann et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…MT polymerisation is primarily understood in vitro , where MTs can undergo polymerisation in the presence of nucleation seeds and tubulin heterodimers; the addition of catalytic factors such as CLASPs, stathmins, tau, Eb proteins or XMAP215 can enhance and refine the process (Aher et al , 2020; Al-Bassam et al , 2010; Brouhard et al , 2008; Drechsel et al , 1992; Li et al , 2012; Manna et al , 2009; Zanic et al , 2013). However, we do not know whether mechanisms observed in reconstitution assays are biologically relevant in the context of axons (Voelzmann et al ., 2016), especially when considering that none of the above-mentioned factors has genetic links to human neurological disorders on OMIM® (Online Mendelian Inheritance in Man), except Tau/MAPT which executes numerous disease-relevant functions also when detached from MTs (Morris et al , 2011).…”

Section: Introductionmentioning

confidence: 99%

Tau, XMAP215/Msps and Eb1 co-operate interdependently to regulate microtubule polymerisation and bundle formation in axons

Hahn

Voelzmann

Parkin

et al. 2020

Preprint

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Axons are the enormously long cable-like cellular processes of neurons that wire nervous systems and have to survive for up to a century in humans. We lose ~40% of axons towards high age and far more in neurodegenerative diseases. Sustaining axons requires axonal transport and dynamic morphogenetic changes, both crucially dependent on bundles of microtubules that run all along axons. How polymerisation is regulated to form, repair and replace microtubules in these bundles during axon development and maintenance is virtually unknown. Here, we show in axons of Drosophila and Xenopus neurons alike that Eb1, XMAP215/Msps and Tau are key players which operate as one functional unit to promote microtubule polymerisation. Eb1 and XMAP215/Msps are interdependent core factors at the microtubule tip, whereas Tau outcompetes Eb1 binding at microtubule lattices, thus preventing its pool depletion at polymerising plus ends. In agreement with their closely interwoven functions, the three factors show the same combination of axonal loss-of-function mutant phenotypes including: (1) reduced microtubule polymerisation dynamics and shorter axon growth, indicating their importance for upholding microtubule mass in axons; (2) prominent deterioration of parallel microtubule bundles into disorganised curled conformations, indicating their key roles in promoting essential axonal architecture. We show the latter to occur through Eb1- and spectraplakin-dependent guidance of extending microtubules. We conclude that Eb1, XMAP215/Msps and Tau jointly promote microtubule polymerisation, important to regulate the quantity and bundled organisation of microtubules and offering new ways to think about developmental and degenerative axon pathologies and how to treat them.

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“…Using this approach, Coombes et al 52 presented evidence that the taper evolves during microtubule growth from a seed and reaches a steady-state length that varies with the free tubulin concentration. This approach has been extended to show that microtubule plus tips are elongated in cells and when microtubules are grown in vitro in the presence of regulatory proteins 11,54,55 . However, using similar approaches, Maurer et al 20 concluded that taper lengths for microtubules grown under standard conditions in vitro were below the detection limit of $180 nm for this technique, which they established using model convolution.…”

Section: Tapered Microtubulesmentioning

confidence: 99%