Phosphoregulation of Kinesins Involved in Long-Range Intracellular Transport

Kumari, Diksha; Ray, Krishanu

doi:10.3389/fcell.2022.873164

Cited by 14 publications

(10 citation statements)

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“…The mechanisms of on-vesicle kinesin regulation are an emerging frontier in kinesin biology ( Verhey and Hammond, 2009 ; Maday et al. , 2014 ; Cason and Holzbaur, 2022 ; Kumari and Ray, 2022 ; Nabb and Bentley, 2022 ). Kinesin autoinhibition was first described for Kinesin-1 ( Verhey et al.…”

Section: Discussionmentioning

confidence: 99%

KAP is the neuronal organelle adaptor for Kinesin-2 KIF3AB and KIF3AC

Garbouchian

Gilbert

Bentley

2022

MBoC

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Kinesin-driven organelle transport is crucial for neuron development and maintenance, yet the mechanisms by which kinesins specifically bind their organelle cargoes remain undefined. In contrast to other transport kinesins, the neuronal function and specific organelle adaptors of heterodimeric Kinesin-2 family members KIF3AB and KIF3AC remain unknown. We developed a novel microscopy-based assay to define protein–protein interactions in intact neurons. The experiments found that KIF3AB and KIF3AC both bind kinesin-associated protein (KAP). These interactions are mediated by the distal C-terminal tail regions and not the coiled-coil domain. We used live-cell imaging in cultured hippocampal neurons to define the localization and trafficking parameters of KIF3AB and KIF3AC organelle populations. We discovered that KIF3AB/KAP and KIF3AC/KAP bind the same organelle populations and defined their transport parameters in axons and dendrites. The results also show that ∼12% of KIF3 organelles contain the RNA binding protein, adenomatous polyposis coli. These data point towards a model in which KIF3AB and KIF3AC use KAP as their neuronal organelle adaptor and that these kinesins mediate transport of a range of organelles.

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Section: Discussionmentioning

confidence: 99%

KAP is the neuronal organelle adaptor for Kinesin-2 KIF3AB and KIF3AC

Garbouchian

Gilbert

Bentley

2022

MBoC

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“…A second mechanism may be that inactive KIF3/KAP binds organelles until an external signal triggers activation. The mechanisms of on-vesicle kinesin regulation are an emerging frontier in kinesin biology (Nabb and Bentley, 2022; Kumari and Ray, 2022; Verhey and Hammond, 2009; Maday et al, 2014; Cason and Holzbaur, 2022). Kinesin autoinhibition was first described for Kinesin-1 (Verhey et al, 1998) and is thought to be a regulatory mechanism for most—if not all— transport kinesins (Verhey and Hammond, 2009; Verhey et al, 2011; Twelvetrees, 2020; Chiba et al, 2022; Keren-Kaplan and Bonifacino, 2021; Bianchi et al, 2016; Ren et al, 2018; Fu and Holzbaur, 2013; Twelvetrees et al, 2019), including heterodimeric Kinesin-2 (Hammond et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

KAP is the neuronal organelle adaptor for Kinesin-2 KIF3AB and KIF3AC

Garbouchian

Gilbert

Bentley

2022

Preprint

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Kinesin-driven organelle transport is crucial for neuron development and maintenance, yet the mechanisms by which kinesins specifically bind their organelle cargoes remain undefined. In contrast to other transport kinesins, the neuronal function and specific organelle adaptors of heterodimeric Kinesin-2 family members KIF3AB and KIF3AC remain unknown. We developed a novel microscopy-based assay to define protein-protein interactions in intact neurons. The experiments found that KIF3AB and KIF3AC both bind KAP. These interactions are mediated by the distal C-terminal tail regions and not the coiled-coil domain. We used live-cell imaging in cultured hippocampal neurons to define the localization and trafficking parameters of KIF3AB and KIF3AC organelle populations. We discovered that KIF3AB/KAP and KIF3AC/KAP bind the same organelle populations and defined their transport parameters in axons and dendrites. The results also show that ~12% of KIF3 organelles contain the RNA binding protein, adenomatous polyposis coli. These data point towards a model in which KIF3AB and KIF3AC use KAP as their neuronal organelle adaptor and that these kinesins mediate transport of a range of organelles.

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“…They found that a subunit of heterotrimeric kinesin that drives IFT anterograde motion, FLA8/KIF3B, is phosphorylated by a calcium-dependent protein kinase (CDPK1), and this phosphorylation negatively regulates IFT injection into flagella. Because this work provides a potential missing link in understanding the ion-current model, calcium-mediated regulation of IFT entry has increasingly been viewed as a likely means of regulating IFT in response to flagellar length ( Engelke et al, 2019 ; Jiang et al, 2019 ; Kumari and Ray, 2022 ; Lechtreck et al, 2017 ; Liang et al, 2018 ). There is thus a pressing need to test whether this model does in fact account for IFT regulation as a function of length.…”

Section: Introductionmentioning

confidence: 99%

Testing the ion-current model for flagellar length sensing and IFT regulation

Ishikawa

Moore

Diener

et al. 2023

eLife

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Eukaryotic cilia and flagella are microtubule-based organelles whose relatively simple shape makes them ideal for investigating the fundamental question of organelle size regulation. Most of the flagellar materials are transported from the cell body via an active transport process called intraflagellar transport (IFT). The rate of IFT entry into flagella, known as IFT injection, has been shown to negatively correlate with flagellar length. However, it remains unknown how the cell measures the length of its flagella and controls IFT injection. One of the most-discussed theoretical models for length sensing to control IFT is the ion-current model, which posits that there is a uniform distribution of Ca2+ channels along the flagellum and that the Ca2+ current from the flagellum into the cell body increases linearly with flagellar length. In this model, the cell uses the Ca2+ current to negatively regulate IFT injection. The recent discovery that IFT entry into flagella is regulated by the phosphorylation of kinesin through a calcium-dependent protein kinase has provided further impetus for the ion-current model. To test this model, we measured and manipulated the levels of Ca2+ inside of Chlamydomonas flagella and quantified IFT injection. Although the concentration of Ca2+ inside of flagella was weakly correlated with the length of flagella, we found that IFT injection was reduced in calcium-deficient flagella, rather than increased as the model predicted, and that variation in IFT injection was uncorrelated with the occurrence of flagellar Ca2+ spikes. Thus, Ca2+ does not appear to function as a negative regulator of IFT injection, hence it cannot form the basis of a stable length control system.

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Phosphoregulation of Kinesins Involved in Long-Range Intracellular Transport

Cited by 14 publications

References 232 publications

KAP is the neuronal organelle adaptor for Kinesin-2 KIF3AB and KIF3AC

KAP is the neuronal organelle adaptor for Kinesin-2 KIF3AB and KIF3AC

KAP is the neuronal organelle adaptor for Kinesin-2 KIF3AB and KIF3AC

Testing the ion-current model for flagellar length sensing and IFT regulation

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