Regulation of in vivo dynein force production by CDK5 and 14-3-3ε and KIAA0528

Chapman, Dail; Reddy, Babu J.N.; Huy, Bunchhin; Bovyn, Matthew J.; Cruz, Stephen John S.; Al-Shammari, Zahraa M.; Han, Han; Wang, Wenqi; Smith, Deanna S.; Gross, Steven P.

doi:10.1038/s41467-018-08110-z

Cited by 21 publications

(13 citation statements)

References 63 publications

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“…Importantly, we find that KASH5 recruits LIS1 as well as dynein and dynactin, and that LIS1 is needed for dynactin recruitment to KASH5. LIS1 is crucial for dynein function where high force is needed (Chapman et al, 2019; Markus et al, 2020; Pandey and Smith, 2011; Reddy et al, 2016; Yi et al, 2011), and has recently been shown to increase force generation of dynein-dynactin complexes in vitro by promoting the recruitment of two dynein motors per dynactin (Elshenawy et al, 2020; Htet et al, 2020; Markus et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein

Garner

Salter

Lau

et al. 2022

Preprint

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Cytoplasmic dynein-driven movement of chromosomes during prophase I of meiosis is essential for synapsis and genetic exchange. Dynein connects to chromosome telomeres via KASH5 and SUN1/2, which span the outer and inner nuclear envelopes, respectively. Here, we show that KASH5 promotes dynein motility in vitro, and cytosolic KASH5 inhibits dynein’s interphase functions. KASH5 interacts with either dynein light intermediate chain (DYNC1LI1 or DYNC1LI2) via a conserved linker-helix in the LIC C-terminal, and this region is also needed for dynein’s recruitment to other cellular membranes. KASH5’s N-terminal EF-hands are essential, as the interaction with dynein is disrupted by mutation of key calcium-binding residues, although it is not regulated by cellular calcium levels. Dynein can be recruited to KASH5 at the nuclear envelope independently of dynactin, while LIS1 is essential for dynactin incorporation into the KASH5-dynein complex. Altogether, we show that the trans-membrane protein KASH5 is an activating adaptor for dynein, and shed light on the hierarchy of assembly of KASH5-dynein-dynactin complexes.

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Section: Discussionmentioning

confidence: 99%

The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein

Garner

Salter

Lau

et al. 2022

Preprint

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“…However, multiple Dynein adaptors such as Ndel1L, Lis1 or BICD, have been reported to be phosphorylated by either kinases 47,48,32 and could be the link to Bin1. Additional layers of regulation are certainly at play as both Cdk5 and GSK3β regulate Dynein processivity, in addition to cargo loading 32,33,49,50 .…”

Section: Discussionmentioning

confidence: 99%

Cdk5 and GSK3β inhibit Fast Endophilin-Mediated Endocytosis

Ferreira

Casamento

Roas

et al. 2020

Preprint

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20Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Parallel to 21 Clathrin-mediated endocytosis, additional Clathrin-independent endocytic routes exist, including fast 22 Endophilin-mediated endocytosis (FEME). The latter is not constitutively active but requires the 23 activation of selected receptors. In cell culture, however, the high levels of growth factors in the 24 regular culture media induce spontaneous FEME, which can be suppressed upon serum starvation. 25Thus, we predicted a role for protein kinases in this growth factor receptor-mediated regulation of 26 the pathway. Using chemical and genetic inhibition, we found that Cdk5 and GSK3β are negative 27 regulators of FEME. Their inhibition was sufficient to activate FEME promptly in resting cells and 28 boosted the production of endocytic carriers containing β1-adrenergic receptor, following 29 dobutamine addition. We established that the kinases suppress FEME at several levels. They control 30 Dynamin-1 and Dynein recruitment and sorting of cargo receptors such as Plexin A1 and ROBO1 into 31 FEME carriers. They do so by antagonizing the binding of Endophilin to Dynamin-1 as well as to 32 Collapsin response mediator protein 4 (CRMP4), a Plexin A1 adaptor. Cdk5 and GSK3β also hamper 33 the binding and recruitment of Dynein onto FEME carriers by Bin1. Interestingly, we found that 34 GSK3β binds to Endophilin, thus imposing a local regulation of FEME. Collectively, these findings 35 place the two kinases as key regulators of FEME, licensing cells for rapid uptake by the pathway only 36 upon when Cdk5 and GSK3β activity is low. 38 39Clathrin-mediated endocytosis (CME) is the major uptake pathway in resting cells 1,2 but additional Clathrin-40 independent endocytic (CIE) routes, including fast Endophilin-mediated endocytosis (FEME), perform 41 specific functions or internalize various cargoes 3,4 . FEME is not constitutively active but is triggered upon the 42 stimulation of selected cell surface receptors by their ligands 5 . These include G-protein coupled receptors 43 (e.g. β1-adrenergic receptor, hereafter β1AR), receptor tyrosine kinases (e.g. epidermal growth factor 44 receptor, EGFR) or cytokine receptors (e.g. Interleukin-2 receptor) 5 . In resting cells, FEME is primed by a 45 cascade of molecular events starting with active, GTP-loaded, Cdc42 recruiting CIP4/FBP17 that engage the 46 5'-phosphatase SHIP2 and Lamellipodin (Lpd). The latter then concentrates Endophilin into clusters on 47 discrete locations of the plasma membrane 6 . In absence of receptor activation, the clusters dissemble 48 quickly (after 5 to 15 sec) upon local recruitment of the Cdc42 GTPase-activating proteins RICH1, SH3BP1 49 or Oligophrenin 6 New priming cycles start nearby, constantly priming the plasma membrane for FEME. Upon 50 activation, receptors are quickly sorted into pre-existing Endophilin clusters that then bud to form FEME 51 carriers, which are Clathrin-negative, Endophilin-positive assemblies (EPAs) found in the cytosol. The en...

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“…However, the physiological and functional relevance of reduced dynein protein expression coupled with sustained retrograde transport remains to be studied further. It has been shown that CDK5 regulates dynein force adaptation for mitochondria and lysosomes (Chapman et al, 2019) by stabilizing the dynein-NudEL-LIS1 complex to enhance dynein force production. Since CDK5 is also activated in AD (Liu et al, 2016) and phosphorylates tau (Kimura et al, 2014), it is likely that decreased dynein in P301L cells might be an early adaptation mechanism to fine-tune the transport from being too robust in the retrograde direction.…”

Section: Discussionmentioning

confidence: 99%

“…To investigate the molecular mechanisms underlying reduced mitochondrial transport, we have generated a heterologous tauopathy model by overexpressing P301L in COS7 cells. COS cells provide an excellent model for understanding signaling aspects of tau-mediated transport, as tau is not present in COS cells (Chapman et al, 2019), ruling out the possible confounding effects of tau on microtubules. Cells expressing P301L show increased phosphorylation compared to either wild-type or GFP expressing cells (Figures 3A,C).…”

Section: Overexpression Of P301l Impairs Parkin Translocation To Mito...mentioning

confidence: 99%

Decreased anterograde transport coupled with sustained retrograde transport contributes to reduced axonal mitochondrial density in tauopathy neurons

Sabui

Biswas²,

Somvanshi³

et al. 2022

Front. Mol. Neurosci.

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Mitochondria are essential organelle required for neuronal homeostasis. Mitochondria supply ATP and buffer calcium at synaptic terminals. However, the complex structural geometry of neurons poses a unique challenge in transporting mitochondria to synaptic terminals. Kinesin motors supply mitochondria to the axonal compartments, while cytoplasmic dynein is required for retrograde transport. Despite the importance of presynaptic mitochondria, how and whether axonal mitochondrial transport and distribution are altered in tauopathy neurons remain poorly studied. In the current study, we have shown that anterograde transport of mitochondria is reduced in P301L neurons, while there is no change in the retrograde transport. Consistently, axonal mitochondrial abundance is reduced in P301L neurons. We further studied the possible role of two opposing motor proteins on mitochondrial transport and found that mitochondrial association of kinesin is decreased significantly in P301L cells. Interestingly, fitting our experimental data into mathematical equations suggested a possible rise in dynein activity to maintain retrograde flux in P301L cells. Our data indicate that decreased kinesin-mediated transport coupled with sustained retrograde transport might reduce axonal mitochondria in tauopathy neurons, thus contributing to the synaptic deficits in Alzheimer’s disease (AD) and other tauopathies.

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Regulation of in vivo dynein force production by CDK5 and 14-3-3ε and KIAA0528

Cited by 21 publications

References 63 publications

The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein

The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein

Cdk5 and GSK3β inhibit Fast Endophilin-Mediated Endocytosis

Decreased anterograde transport coupled with sustained retrograde transport contributes to reduced axonal mitochondrial density in tauopathy neurons

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