Kinesin-1 Regulates Microtubule Dynamics via a c-Jun N-terminal Kinase-dependent Mechanism

Daire, Vanessa; Giustiniani, Julien; Leroy-Gori, Ingrid; Quesnoit, Mélanie; Drevensek, Stéphanie; Dimitrov, Ariane; Perez, Franck; Poüs, Christian

doi:10.1074/jbc.m109.007906

Cited by 51 publications

(45 citation statements)

References 45 publications

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“…Conversely, enhancing MT acetylation leads to the recruitment of kinesin-1 and dynein motors to MTs, thereby stimulating anterograde and retrograde transport in vitro and in vivo (28,47). Moreover, kinesin-1 stimulates MT elongation and maintains MT integrity by allowing the activation of c-Jun N-terminal kinase (48). It is therefore possible that increased MT acetylation rescues tau-induced MT defects by recruiting motor proteins to MTs, but this possibility needs to be confirmed.…”

Section: Discussionmentioning

confidence: 95%

HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila

Xiong

Zhao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Neurons from the brains of Alzheimer's disease (AD) and related tauopathy patients contain neurofibrillary tangles composed of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs); however, tau hyperphosphorylation leads to loss of this function with consequent MT destabilization and neuronal dysfunction. Accordingly, MT-stabilizing drugs such as paclitaxel and epothilone D have been shown as possible therapies for AD and related tauopathies. However, MT-stabilizing drugs have common side effects such as neuropathy and neutropenia. To find previously undescribed suppressors of tau-induced MT defects, we established a Drosophila model ectopically expressing human tau in muscle cells, which allow for clear visualization of the MT network. Overexpressed tau was hyperphosphorylated and resulted in decreased MT density and greater fragmentation, consistent with previous reports in AD patients and mouse models. From a genetic screen, we found that a histone deacetylase 6 (HDAC6) null mutation rescued tau-induced MT defects in both muscles and neurons. Genetic and pharmacological inhibition of the tubulin-specific deacetylase activity of HDAC6 indicates that the rescue effect may be mediated by increased MT acetylation. These findings reveal HDAC6 as a unique potential drug target for AD and related tauopathies.disease model | genetic study T au is a neuronal microtubule-associated protein (MAP) that binds to and stabilizes microtubules (MTs). However, in Alzheimer's disease (AD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and other tauopathies, tau is hyperphosphorylated and aggregated into straight or paired helical filaments (PHFs) in the cell bodies and neurites of central neurons (1). In vitro biochemical studies demonstrated that hyperphosphorylated tau does not bind to MTs and thus does not promote MT stability (2, 3). Furthermore, mutations in tau lead to FTDP-17, and some of these mutations have been reported to reduce MT-tau binding affinity (4, 5), underscoring the importance of loss of normal MT-stabilizing function of tau in the pathogenesis of neurodegenerative tauopathies.MTs are disrupted in the brains of patients and animal models of tauopathies. For example, MT density was reduced in both hippocampal neurons of transgenic mice expressing V337M mutant human tau and the spinal ventral root axons of transgenic mice expressing the smallest isoform of human tau (6, 7). Furthermore, administration of the MT-stabilizing agents paclitaxel and epothilone D to human tau-expressing mice results in improved MT density and axonal integrity (8), as well as enhanced cognitive performance (9, 10). However, paclitaxel has poor blood-brain barrier (BBB) permeability and thus is unsuitable for clinical treatment of brain diseases. Epothilone D is BBB-permeable; however, as a general MT stabilizer and genotoxic agent, it may have side effects such as neuropathy and neutropenia.In this study, we aimed to find new strategies for mitigating tau toxicity by identifying...

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Section: Discussionmentioning

confidence: 95%

HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila

Xiong

Zhao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, Rab5 regulates the activity of c-Jun N-terminal kinase (JNK) during neuronal migration (76). JNK is involved in MT dynamics during axonal transport via interactions with kinesin-1 to promote MT growth, elongation, and rescue (77). An additional upstream regulator of JNK, Wallenda, regulates the linkage between kinesin and its cargo during axonal transport, likely via JNK activation (78).…”

Section: Figmentioning

confidence: 99%

Multiparametric Analysis of CLASP-Interacting Protein Functions during Interphase Microtubule Dynamics

Long

Bagonis

Lowery

et al. 2013

Molecular and Cellular Biology

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The microtubule (MT) plus-end tracking protein (؉TIP) CLASP mediates dynamic cellular behaviors and interacts with numerous cytoplasmic proteins. While the influence of some CLASP interactors on MT behavior is known, a comprehensive survey of the proteins in the CLASP interactome as MT regulators is missing. Ultimately, we are interested in understanding how CLASP collaborates with functionally linked proteins to regulate MT dynamics. Here, we utilize multiparametric analysis of time-lapse MT ؉TIP imaging data acquired in Drosophila melanogaster S2R؉ cells to assess the effects on individual microtubule dynamics for RNA interference-mediated depletion of 48 gene products previously identified to be in vivo genetic CLASP interactors. While our analysis corroborates previously described functions of several known CLASP interactors, its multiparametric resolution reveals more detailed functional profiles (fingerprints) that allow us to precisely classify the roles that CLASP-interacting genes play in MT regulation. Using these data, we identify subnetworks of proteins with novel yet overlapping MT-regulatory roles and also uncover subtle distinctions between the functions of proteins previously thought to act via similar mechanisms. The orchestration of cytoskeletal dynamics is critical for a broad range of cellular behaviors, including mitosis, polarity, motility, morphogenesis, and cell-cell interaction (1-3). Microtubule (MT) polymer networks participate in numerous signaling pathways, often helping to assemble and/or deliver effector protein complexes and to define the spatial organization of cellular responses. Many classes of cytoskeletal binding proteins regulate the configuration of MT arrays and often interact with other protein networks. However, our understanding of how these extended effector networks function to control cytoskeletal dynamics is still limited. Large-scale screens for MT regulators have primarily relied on endpoint phenotypes that affect mitosis (4-6). The mitotic spindle is a unique apparatus whose gross architecture can be severely disturbed by accumulated effects of altered MT dynamics and thus offers a simple readout for such studies. However, these readouts report screening hits only on the basis of indirect MT phenotypes in a large complex system without pinpointing the actual role that they play in terms of bona fide MT regulation. Direct detection of altered MT dynamics has been much more challenging. For this reason, we adopted a quantitative live-imaging approach that allowed us to identify with single-MT resolution shifts in MT dynamics induced by RNA interference (RNAi)-mediated depletion of putative MT regulators.CLASP (cytoplasmic linker protein [CLIP]-associated protein) is a well-conserved MT plus-end interacting protein (ϩTIP), which modulates dynamic instability and facilitates the interaction of MTs with other cellular structures, including the cell cortex (7, 8) and kinetochores (9-11). CLASP functions as an MT-stabilizing factor, promoting MT rescue both in cultured ...

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“…Most kinesins were thought to promote microtubule disassembly ever since the first catastrophe kinesin XKCM1 was discovered in frog eggs by Walczak et al (28). However, Daire et al (29) have recently identified a novel kinesin-1 that promotes microtubule assembly. Our study showed that B23 binds to the motor domain of the kinesin Eg5, which was known to contribute solely to its length-dependent control of kinetochore microtubule and works as a brake of MT array (2,3).…”

Section: Discussionmentioning

confidence: 99%

Nucleophosmin/B23 Inhibits Eg5-mediated Microtubule Depolymerization by Inactivating Its ATPase Activity

Wang¹,

Gao²,

Huang

et al. 2010

Journal of Biological Chemistry

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Nucleophosmin/B23, an abundant nucleolar protein, plays multiple roles in cell growth and proliferation, and yet, little has been studied about its function in regulating dynamics of microtubules. Here, we report that B23 directly interacts with Eg5, a member of the kinesin family, in the cytosol. The DNA/RNA binding domain of B23 and the motor domain of Eg5 were found to be involved in their interaction. Both in vivo and in vitro evidences showed that B23 acts as an upstream regulator of Eg5 in promoting microtubule polymerization. Moreover, we further demonstrated that B23 regulates microtubule dynamics by directly inhibiting Eg5 ATPase activity. Microtubule (MT)3 dynamics exist in two major states, either growing or shrinking, and switch stochastically between these two states. The transition from growth to shrinkage is called a catastrophe, and in contrast, transition from shrinkage to growth is called a rescue (1). Both growing and shrinking processes are regulated by various cellular factors that stabilize and/or destabilize the MT lattice. Eg5 (also known as kinesin-5, KIF11), a motor protein that belongs to the kinesin-like protein family, was recently reported to mediate length-dependent control of MT assembly (2, 3). It is proposed that kinesins disassemble longer kinetochore microtubule by generating a concentration gradient along a MT and hydrolyze ATP to move toward the plus (ϩ) end, where it causes MT depolymerization (4, 5). It is now a well established fact that kinesin-related proteins can destabilize microtubules, and the kinesins that destabilize the ends of microtubules are known as "catastrophe kinesins" (6). However, how catastrophe kinesins are regulated remains to be further investigated. Nucleophosmin (also known as B23) is a multifunctional phosphoprotein that shuttles rapidly between the nucleus and the cytoplasm (7, 8). B23 provokes cell proliferation and transformation, and B23 is frequently mutated in many different tumor types such as acute myeloid leukemia (AML) (9 -11). Despite the fact that its functions inside of the nucleus have been well studied, the functional role of B23 in the cytoplasm remains elusive. Previous studies have shown that B23 regulates centrosome duplication during mitosis (12-14), which hints that the protein B23 also may play roles in the global control of the MT lattice.In this study, we identified that B23/nucleophosmin interacts directly with Eg5, and through this interaction, B23 inhibited ATPase activity of the Eg5 motor domain and thus down-regulated the Eg5-mediated ATP-dependent microtubule catastrophe. The physiological effects of Eg5 on microtubules are more significant upon the elimination of B23 protein levels, indicating that B23 normally plays a protective role in MT assembly. EXPERIMENTAL PROCEDURESCell Culture, Drug Treatments, Transfection, and siRNACells were maintained in Dulbecco's modified Eagle's medium (Invitrogen) containing 10% fetal bovine serum. Cells were transfected by Lipofectamine 2000 (Invitrogen) according to the manufacture...

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Kinesin-1 Regulates Microtubule Dynamics via a c-Jun N-terminal Kinase-dependent Mechanism

Cited by 51 publications

References 45 publications

HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila

HDAC6 mutations rescue human tau-induced microtubule defects in Drosophila

Multiparametric Analysis of CLASP-Interacting Protein Functions during Interphase Microtubule Dynamics

Nucleophosmin/B23 Inhibits Eg5-mediated Microtubule Depolymerization by Inactivating Its ATPase Activity

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