VezA/vezatin facilitates proper assembly of the dynactin complex in vivo DOI Creative Commons
Jun Zhang, Rongde Qiu,

Sean Xie

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(11), P. 114943 - 114943

Published: Nov. 1, 2024

Cytoplasmic dynein-mediated intracellular transport needs the multi-component dynactin complex for cargo binding and motor activation. However, cellular factors involved in assembly remain unexplored. Here, we found Aspergillus nidulans that vezatin homolog VezA is important assembly. affects microtubule plus-end accumulation of dynein before cargo-adapter-mediated activation, two processes both need dynactin. The contains multiple components, including p150, p50, an Arp1 (actin-related protein 1) mini-filament associated with a pointed-end sub-complex. physically interacts either directly or indirectly. Loss significantly decreases amount pulled down proteins, as well levels p50 p150 cell extract. Using various mutants, further revealed process must be highly coordinated. Together, these results shed light on vivo.

Language: Английский

Molecular mechanism of dynein-dynactin complex assembly by LIS1 DOI
Kashish Singh, Clinton K. Lau, Giulia Manigrasso

et al.

Science, Journal Year: 2024, Volume and Issue: 383(6690)

Published: March 28, 2024

Cytoplasmic dynein is a microtubule motor vital for cellular organization and division. It functions as ~4-megadalton complex containing its cofactor dynactin cargo-specific coiled-coil adaptor. However, how recognize diverse adaptors, they interact with each other during formation, the role of critical regulators such lissencephaly-1 (LIS1) protein remain unclear. In this study, we determined cryo–electron microscopy structure dynein-dynactin on microtubules LIS1 lysosomal adaptor JIP3. This reveals molecular basis interactions occurring activation. We show JIP3 activates despite atypical architecture. Unexpectedly, binds dynactin’s p150 subunit, tethering it along length dynein. Our data suggest that constrain to ensure efficient formation.

Language: Английский

Citations

27
Dynein and dynactin move long-range but are delivered separately to the axon tip DOI Creative Commons
Alexander D. Fellows, Michaela Bruntraeger, Thomas Burgold

et al.

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(5)

Published: Feb. 6, 2024

Axonal transport is essential for neuronal survival. This driven by microtubule motors including dynein, which transports cargo from the axon tip back to cell body. function requires its cofactor dynactin and regulators LIS1 NDEL1. Due difficulties imaging dynein at a single-molecule level, it unclear how this motor coordinate along length of axon. Here, we use neuron-inducible human stem line (NGN2-OPTi-OX) endogenously tag components visualize them near-single molecule regime. In retrograde direction, find that can move entire (>500 µm). Furthermore, NDEL1 also undergo long-distance movement, despite being mainly implicated with initiation transport. Intriguingly, in anterograde dynein/LIS1 moves faster than dynactin/NDEL1, consistent on different cargos. Therefore, neurons ensure efficient holding dynein/dynactin cargos over long distances but keeping separate until required.

Language: Английский

Citations

12
The Power of Three: Dynactin associates with three dyneins under load for greater force production DOI Open Access
Lu Rao, Xinglei Liu,

Mirjam Arnold

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 18, 2025

Abstract Cytoplasmic dynein is an essential microtubule motor protein that powers organelle transport and mitotic spindle assembly. Its activity depends on dynein-dynactin-cargo adaptor complexes, such as dynein-dynactin-BicD2 (DDB), which typically function with two motors. We show mechanical tension recruits a third via auxiliary BicD binding the light intermediate chain of dynein, stabilizing multi-dynein assemblies enhancing force generation. Lis1 prevents from transitioning into force-limiting phi-like conformation, allowing single-dynein DDB to sustain forces up ∼4.5 pN, whereas generation often ends at ∼2.5 pN without Lis1. Complexes or three dyneins generate ∼7 ∼9 respectively, consistent staggered arrangement enhances collective output. Under load, primarily takes ∼8 nm steps, challenging existing coordination models. These findings reveal adaptive mechanisms enable robust intracellular under varying demands.

Language: Английский

Citations

1
NuMA is a mitotic adaptor protein that activates dynein and connects it to microtubule minus ends DOI
Sabina Colombo,

Christel Michel,

Silvia Speroni

et al.

The Journal of Cell Biology, Journal Year: 2025, Volume and Issue: 224(4)

Published: Jan. 22, 2025

Nuclear mitotic apparatus protein (NuMA) is indispensable for the functions of major microtubule minus-end directed motor cytoplasmic dynein 1. NuMA and are both essential correct spindle pole organization. How these proteins cooperate to gather minus ends at poles remains unclear. Here, we use microscopy-based in vitro reconstitutions demonstrate that a adaptor, activating processive motility together with dynein's cofactors dynactin Lissencephaly-1 (Lis1). Additionally, find binds stabilizes ends, allowing dynein/dynactin/NuMA transport as cargo other ends. We further show microtubule-nucleating γ-tubulin ring complex (γTuRC) hinders binding only caps γTuRC-nucleated microtubules after γTuRC release. These results provide new mechanistic insight into how dynein, dynactin, NuMA, Lis1 uncapping organize cells.

Language: Английский

Citations

1
Cargo adaptor identity controls the mechanism and kinetics of dynein activation DOI Creative Commons
John P. Gillies, Saffron R. Little,

Aravintha Siva

et al.

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108358 - 108358

Published: Feb. 1, 2025

Language: Английский

Citations

1
UNC-16 interacts with LRK-1 and WDFY-3 to regulate the termination of axon growth DOI
C Drózd, Tamjid A. Chowdhury, Christopher C. Quinn

et al.

Genetics, Journal Year: 2024, Volume and Issue: 227(2)

Published: April 6, 2024

In humans, MAPK8IP3 (also known as JIP3) is a neurodevelopmental disorder-associated gene. Caenorhabditis elegans, the UNC-16 ortholog of protein can regulate termination axon growth. However, its role in this process not well understood. Here, we report that promotes through includes LRK-1 (LRRK-1/LRRK-2) kinase and WDFY-3 (WDFY3/Alfy) selective autophagy protein. Genetic analysis suggests an interaction between RH1 domain dynein complex. Loss unc-16 function causes accumulation late endosomes specifically distal axon. Moreover, observe synergistic interactions loss disruptors endolysosomal function, indicating system termination. We also find defects caused by require genetic pathway lrk-1 wdfy-3, 2 genes have been implicated autophagy. These observations suggest model where interacting with to WDFY-3.

Language: Английский

Citations

4
Disruptions in axonal lysosome transport and its contribution to neurological disease DOI Creative Commons

Jean‐Michel Paumier,

Swetha Gowrishankar

Current Opinion in Cell Biology, Journal Year: 2024, Volume and Issue: 89, P. 102382 - 102382

Published: June 20, 2024

Lysosomes are central to the maintenance of protein and organelle homeostasis in cells. Optimal lysosome function is particularly critical for neurons which long-lived, non-dividing highly polarized with specialized compartments such as axons dendrites distinct architecture, cargo, turnover requirements. In recent years, there has been a growing appreciation role played by axonal transport regulating neuronal development, its functioning. Perturbations optimal abundance leading either strong accumulations or dearth lysosomes both linked altered health this review we highlight how two regulators abundance, small GTPase Arl8 adaptor JIP3, aid maintaining alterations their levels activity could contribute neurodevelopmental neurodegenerative diseases.

Language: Английский

Citations

4
Anti-Parkinsonian Drugs Rescue Locomotor Deficits in JIP3 Knockout Zebrafish: Implications for Treating Patients with MAPK8IP3-related Neurodevelopmental Disorders DOI Creative Commons
Aleksandra Foksinska, J. Paige Souder,

Gabrielle Smith

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

ABSTRACT MAPK8IP3- related neurodevelopmental disorders are a spectrum of rare conditions caused by de novo mutations in the MAPK8IP3 gene that encodes JIP3 protein. These associated with symptoms manifest children and cause brain abnormalities, profound intellectual disabilities, movement disorders, developmental delays. is required for axonal transport proteins organelles between soma synaptic terminal neurons, process critical normal development function. Homozygous loss-of-function lead to impaired aggregation cargo, which result swelling stunted elongation. Despite these severe outcomes, disease mechanisms poorly understood, no current treatments available. Here we conduct thorough morphological, behavioral, motility phenotyping knockout zebrafish identify locomotor deficits morphological abnormalities. To treatment options, used insights from expert clinicians artificial intelligence tool, mediKanren, drug candidates hypothesized improve patient or compensate loss at molecular level. We then prioritized drugs FDA-approved, safe children, readily collective efforts identified amantadine levodopa as candidate therapies rescued motor phenotypes zebrafish.

Language: Английский

Citations

0
Development of near-isogenic line of dwarf gene Cldw-1 and transcriptome analysis in watermelon (Citrullus lanatus) DOI Creative Commons

Minjuan Zhang,

Wenkai Yan, Mengyuan Yan

et al.

Scientia Horticulturae, Journal Year: 2025, Volume and Issue: 343, P. 114065 - 114065

Published: March 1, 2025

Language: Английский

Citations

0
Dynactin knockdown leads to synuclein aggregation by blocking autophagy in a zebrafish model of Parkinson's disease DOI Creative Commons

Yongmei Wu,

Qiang Guo,

Jinfan Gan

et al.

Brazilian Journal of Medical and Biological Research, Journal Year: 2025, Volume and Issue: 58

Published: Jan. 1, 2025

Axons of dopaminergic neurons projecting from substantia nigra to striatum are severely affected in the early stage Parkinson's disease (PD), with axonal degeneration preceding loss cell bodies. Our previous study indicated that dysfunctional retrograde transport could lead death resulting PD (10.1111/j.1471-4159.2008.05526.x). However, dynein, as main molecule involved transport, was not affected. This aimed verify hypothesis dynactin rather than dynein may be one key factors PD. Dynactin morpholino used inhibit expression transgenic (Vmat2:GFP) zebrafish, a significant decrease diencephalon dopamine and synuclein aggregation basal plate region. In SH-SY5Y line, dynactin-siRNA knockdown resulted shifting dispersed distribution concentration synapses cytoplasm near axons, fusion rate decreased, especially which blocked α-synuclein autophagy flow. results linked gene dysfunction microtubule system, suggesting contributing

Language: Английский

Citations

0