Distinct retrograde microtubule motor sets drive early and late endosome transport

Villari, Giulia; Bena, Chiara Enrico; Giudice, Marco Del; Gioelli, Noemi; Sandri, Chiara; Camillo, Chiara Di; Fiorio, Alessandra; Bosia, Carla; Serini, Guido

doi:10.15252/embj.2019103661

Cited by 27 publications

(13 citation statements)

References 96 publications

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“…As we have described here, STIM and Orai proteins are increasing recognized as regulating cellular functions beyond the classic Ca 2+ meditated transcription pathways. In addition to metabolic and mitochondrial regulation and cell survival, a protein complex including STIM1 is responsible for trafficking of early and late endosomes ( Villari et al, 2020 ), consistent with its identification as a microtubule plus-end tracking protein. This could have wide ranging implications given the numerous fundamental functions of the endolysosomal system including metabolic signaling, plasma membrane remodeling autophagy and cell migration ( Bonifacino and Neefjes, 2017 ).…”

Section: Discussionmentioning

confidence: 76%

STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases

2022

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Tight spatiotemporal regulation of intracellular Ca2+ plays a critical role in regulating diverse cellular functions including cell survival, metabolism, and transcription. As a result, eukaryotic cells have developed a wide variety of mechanisms for controlling Ca2+ influx and efflux across the plasma membrane as well as Ca2+ release and uptake from intracellular stores. The STIM and Orai protein families comprising of STIM1, STIM2, Orai1, Orai2, and Orai3, are evolutionarily highly conserved proteins that are core components of all mammalian Ca2+ signaling systems. STIM1 and Orai1 are considered key players in the regulation of Store Operated Calcium Entry (SOCE), where release of Ca2+ from intracellular stores such as the Endoplasmic/Sarcoplasmic reticulum (ER/SR) triggers Ca2+ influx across the plasma membrane. SOCE, which has been widely characterized in non-excitable cells, plays a central role in Ca2+-dependent transcriptional regulation. In addition to their role in Ca2+ signaling, STIM1 and Orai1 have been shown to contribute to the regulation of metabolism and mitochondrial function. STIM and Orai proteins are also subject to redox modifications, which influence their activities. Considering their ubiquitous expression, there has been increasing interest in the roles of STIM and Orai proteins in excitable cells such as neurons and myocytes. While controversy remains as to the importance of SOCE in excitable cells, STIM1 and Orai1 are essential for cellular homeostasis and their disruption is linked to various diseases associated with aging such as cardiovascular disease and neurodegeneration. The recent identification of splice variants for most STIM and Orai isoforms while complicating our understanding of their function, may also provide insight into some of the current contradictions on their roles. Therefore, the goal of this review is to describe our current understanding of the molecular regulation of STIM and Orai proteins and their roles in normal physiology and diseases of aging, with a particular focus on heart disease and neurodegeneration.

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Section: Discussionmentioning

confidence: 76%

STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases

2022

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“…Another open question is which kinesins are required for the transport of Hrs and STAM1 under basal conditions, as KIF13A knockdown does not seem to impair this process. Several kinesins in addition to KIF13A and KIF13B, including KIF5A/B/C, KIFC1, and KIF16B, have been implicated in endosomal trafficking ( Bonifacino & Neefjes, 2017 ; Li et al, 2020 ; Villari et al, 2020 ) and may also have roles in the axonal transport of ESCRT-0 proteins. Clearly, additional work is needed to identify other cargoes of KIF13A, as well as the specific motor proteins responsible for anterograde and retrograde transport of Hrs+ vesicles.…”

Section: Discussionmentioning

confidence: 99%

Axonal transport of Hrs is activity dependent and facilitates synaptic vesicle protein degradation

et al. 2022

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Turnover of synaptic vesicle (SV) proteins is vital for the maintenance of healthy and functional synapses. SV protein turnover is driven by neuronal activity in an endosomal sorting complex required for transport (ESCRT)-dependent manner. Here, we characterize a critical step in this process: axonal transport of ESCRT-0 component Hrs, necessary for sorting proteins into the ESCRT pathway and recruiting downstream ESCRT machinery to catalyze multivesicular body (MVB) formation. We find that neuronal activity stimulates the formation of presynaptic endosomes and MVBs, as well as the motility of Hrs+ vesicles in axons and their delivery to SV pools. Hrs+ vesicles co-transport ESCRT-0 component STAM1 and comprise a subset of Rab5+ vesicles, likely representing pro-degradative early endosomes. Furthermore, we identify kinesin motor protein KIF13A as essential for the activity-dependent transport of Hrs to SV pools and the degradation of SV membrane proteins. Together, these data demonstrate a novel activity- and KIF13A-dependent mechanism for mobilizing axonal transport of ESCRT machinery to facilitate the degradation of SV membrane proteins.

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“…The directional movement of vesicles is determined by various microtubule motor proteins that move toward the periphery (e.g., kinesin superfamily proteins KIF5 and KIF3) or perinuclear region (e.g., KIFC1, 2, and 3) depending on the plus or minus orientation of the microtubules to which they attach ( Hirokawa et al, 2009 ; Camlin et al, 2017a ; Muralidharan and Baas, 2019 ). A recent study assessing the microtubule motor control of early endosomes in human endothelial cells demonstrated that simultaneous silencing of KIFC1 and stromal interaction molecule 1 (STIM1) resulted in more peripherally distributed EEA1 positive early endosomes ( Villari et al, 2020 ). Aligning with this, Kifc1 gene and KIFC1 protein expression decreases in the aged oocyte, with functional siRNA-mediated knockdown and pharmacological inhibition of Kifc1 /KIFC1 in young oocytes recapitulating hallmarks of poor oocyte quality such as increased aneuploidy rates ( Mihalas et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

The Impact of Aging on Macroautophagy in the Pre-ovulatory Mouse Oocyte

Peters

Caban

McLaughlin

et al. 2021

Front. Cell Dev. Biol.

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Accompanying the precipitous age-related decline in human female fertility is an increase in the proportion of poor-quality oocytes within the ovary. The macroautophagy pathway, an essential protein degradation mechanism responsible for maintaining cell health, has not yet been thoroughly investigated in this phenomenon. The aim of this study was to characterize the macroautophagy pathway in an established mouse model of oocyte aging using in-depth image analysis-based methods and to determine mechanisms that account for the observed changes. Three autophagy pathway markers were selected for assessment of gene and protein expression in this model: Beclin 1; an initiator of autophagosome formation, Microtubule-associated protein 1 light chain 3B; a constituent of the autophagosome membrane, and lysosomal-associated membrane protein 1; a constituent of the lysosome membrane. Through quantitative image analysis of immunolabeled oocytes, this study revealed impairment of the macroautophagy pathway in the aged oocyte with an attenuation of both autophagosome and lysosome number. Additionally, an accumulation of amphisomes greater than 10 μm2 in area were observed in aging oocytes, and this accumulation was mimicked in oocytes treated with lysosomal inhibitor chloroquine. Overall, these findings implicate lysosomal dysfunction as a prominent mechanism by which these age-related changes may occur and highlight the importance of macroautophagy in maintaining mouse pre-ovulatory oocyte quality. This provides a basis for further investigation of dysfunctional autophagy in poor oocyte quality and for the development of therapeutic or preventative strategies to aid in the maintenance of pre-ovulatory oocyte health.

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Distinct retrograde microtubule motor sets drive early and late endosome transport

Cited by 27 publications

References 96 publications

STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases

STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases

Axonal transport of Hrs is activity dependent and facilitates synaptic vesicle protein degradation

The Impact of Aging on Macroautophagy in the Pre-ovulatory Mouse Oocyte

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