TRAK adaptors regulate the recruitment and activation of dynein and kinesin in mitochondrial transport

Canty, John T.; Hensley, Andrew; Aslan, Merve; Jack, Amanda; Yıldız, Ahmet

doi:10.1038/s41467-023-36945-8

Cited by 34 publications

(16 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mild defect in processivity observed in response to pathogenic HTT-polyQ expansions (Figure 4G) is in close agreement with previous studies [18][19][20][21] . From these data, we hypothesize the defects previously observed in mitochondria transport may be indirect effects due to the health of the neuron, while other scaffolds and adaptors including TRAK/Milton act as the primary regulators of mitochondrial transport 38,39,41 .…”

Section: Mitochondria Motility Is Largely Unaffected By Polyq Expansionsmentioning

confidence: 73%

“…We expected the effect on mitochondrial transport to be mild due to the lack of response to S421 phosphorylation which otherwise impacts the directional bias of neuronal HTT cargoes 24 . In addition, Miro/TRAK have been demonstrated as the primary regulators of mitochondrial transport [38][39][40] . Mitochondria positive for MitoTracker™ were less dynamic than BDNF vesicles or lysosomes, with shorter runs and more stationary cargoes (Figure 4A).…”

Section: Mitochondria Motility Is Largely Unaffected By Polyq Expansionsmentioning

confidence: 99%

See 1 more Smart Citation

Huntingtin polyglutamine expansions misdirect axonal transport by perturbing motor and adaptor recruitment

Prowse,

Turkalj,

Sébastien

et al. 2024

Preprint

View full text Add to dashboard Cite

Huntington's disease (HD) is caused by polyglutamine (polyQ) expansions in huntingtin (HTT). Polyglutamine repeat lengths >35Q lead to neurodegeneration and longer repeats correspond to earlier symptom onset. HTT scaffolds kinesin-1 and dynein to a variety of vesicles and organelles directly and through adaptors. To characterize the effects of HTT polyQ expansions on axonal transport, we tracked BDNF vesicles, mitochondria, and lysosomes in neurons induced from an isogenic set of human stem cell lines with repeat lengths of 30, 45, 65, and 81Q. Mild and intermediate pathogenic polyQ expansions caused increased BDNF motility, while HTT-81Q misdirected BDNF towards the distal tip. In comparison, mitochondria and lysosome transport showed mild defects with polyQHTT. We next examined the effect of polyQHTT in combination with neuroinflammatory stress. Under stress, BDNF cargoes in HTT-30Q neurons were more processive. Stress in HTT-81Q resulted in a stark decrease in the number of BDNF cargoes. However, the few remaining BDNF cargoes displayed more frequent long-range motility in both directions. Under neuroinflammatory stress, lysosomes were more abundant in HTT-81Q neurons, and motile lysosomes moved less processively and had an anterograde bias while lysosomes in HTT-30Q where not strongly affected. To examine how HTT-polyQ expansions altered the motors and adaptors on vesicular cargoes, we isolated BDNF cargoes from neurons and quantified the proteins associated with them. BDNF-endosomes isolated from HTT-81Q neurons associated with 2.5 kinesin-1 and 3.9 HAP1 molecules on average, compared to 1.0 kinesin-1 and 1.0 HAP1 molecule for HTT-30Q neurons. Together, these results show that polyQ expansions in HTT cause aberrant motor and adaptor recruitment to cargoes, resulting in dysregulated transport and responses to neuroinflammatory stress.

show abstract

Section: Mitochondria Motility Is Largely Unaffected By Polyq Expansionsmentioning

confidence: 73%

Section: Mitochondria Motility Is Largely Unaffected By Polyq Expansionsmentioning

confidence: 99%

Huntingtin polyglutamine expansions misdirect axonal transport by perturbing motor and adaptor recruitment

Prowse,

Turkalj,

Sébastien

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Together these observations suggest that a minimal cargo adaptor requires only a coiled coil that can bind and orient the dynein tails so that they can interact with the grooves in dynactin’s filament. Although JIP3 and BICD2 do not absolutely require their Spindly motif in vitro, other adaptors, such as HOOK3 ( 73 ) and TRAK1/2 ( 74 ), do need it. We suspect that these differences reflect the lack of sequence conservation among adaptors, suggesting that some require the reinforcement from the Spindly motif–pointed end interaction to ensure their affinity for the dynein-dynactin complex.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanism of dynein-dynactin complex assembly by LIS1

Singh,

Lau,

Manigrasso

et al. 2024

Science

View full text Add to dashboard Cite

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

show abstract

“…Both Kinesin-1 and Dynein have been shown to be required for transporting mitochondria in Drosophila axons (Pilling et al, 2006). Both motors are linked to mitochondria via the protein Milton (or its human homologs TRAK1 and TRAK2) (Cox and Spradling, 2006;Fenton et al, 2021;Canty et al, 2023). However, the role of Kinesin-1 and Dynein in mitochondrial transport within the egg chamber is relatively unknown.…”

Section: Discussionmentioning

confidence: 99%

dTtc1, a conserved tetratricopeptide repeat protein, is required for maturation of Drosophila egg chambers via its role in stabilizing electron transport chain components

Neiswender

Baker

Veeranan-Karmegam

et al. 2023

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

We recently identified the Drosophila ortholog of TTC1 (dTtc1) as an interacting partner of Egalitarian, an RNA adaptor of the Dynein motor. In order to better understand the function of this relatively uncharacterized protein, we depleted dTtc1 in the Drosophila female germline. Depletion of dTtc1 resulted in defective oogenesis and no mature eggs were produced. A closer examination revealed that mRNA cargoes normally transported by Dynein were relatively unaffected. However, mitochondria in dTtc1 depleted egg chambers displayed an extremely swollen phenotype. Ultrastructural analysis revealed a lack of cristae. These phenotypes were not observed upon disruption of Dynein. Thus, this function of dTtc1 is likely to be Dynein independent. Consistent with a role for dTtc1 in mitochondrial biology, a published proteomics screen revealed that dTtc1 interacts with numerous components of electron transport chain (ETC) complexes. Our results indicate that the expression level of several of these ETC components was significantly reduced upon depletion of dTtc1. Importantly, this phenotype was completely rescued upon expression of wild-type GFP-dTtc1 in the depleted background. Lastly, we demonstrate that the mitochondrial phenotype caused by a lack of dTtc1 is not restricted to the germline but is also observed in somatic tissues. Our model suggests that dTtc1, likely in combination with cytoplasmic chaperones, is required for stabilizing ETC components.

show abstract

TRAK adaptors regulate the recruitment and activation of dynein and kinesin in mitochondrial transport

Cited by 34 publications

References 56 publications

Huntingtin polyglutamine expansions misdirect axonal transport by perturbing motor and adaptor recruitment

Huntingtin polyglutamine expansions misdirect axonal transport by perturbing motor and adaptor recruitment

Molecular mechanism of dynein-dynactin complex assembly by LIS1

dTtc1, a conserved tetratricopeptide repeat protein, is required for maturation of Drosophila egg chambers via its role in stabilizing electron transport chain components

Contact Info

Product

Resources

About