RUFY3 and RUFY4 are ARL8 effectors that couple lysosomes to dynein-dynactin

Keren-Kaplan, Tal; Sarić, Amra; Ghosh, Saikat; Williamson, Chad D.; Jia, Rui; Li, Yan; Bonifacino, Juan S.

doi:10.21203/rs.3.rs-469512/v1

Cited by 3 publications

(2 citation statements)

References 92 publications

(178 reference statements)

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“…Whereas the function of ARL8A is still poorly understood, ARL8B is well studied and known to regulate the kinesin-dependent anterograde movement (towards the cell periphery) of lysosomes (Rosa-Ferreira and Munro, 2011;Khatter et al, 2015). Interestingly, two recent reports showed evidence that ARL8 also regulates long-range endolysosomal retrograde movement (towards the perinuclear region) (Keren-Kaplan et al, 2022;Kumar et al, 2022). ARL8A and ARL8B were found to be upregulated in both luminal A and TNBC cell lines, upon silencing of the Ca 2+ -binding protein TBC1 domain family member 9 (TBC1D9, a RAB GAP), which is associated with an impairment of TNBC progression (Kothari et al, 2021).…”

Section: Arl8mentioning

confidence: 99%

Membrane trafficking alterations in breast cancer progression

Ferreira,

Castanheira,

Escrevente

et al. 2024

Front. Cell Dev. Biol.

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Breast cancer (BC) is the most common type of cancer in women, and remains one of the major causes of death in women worldwide. It is now well established that alterations in membrane trafficking are implicated in BC progression. Indeed, membrane trafficking pathways regulate BC cell proliferation, migration, invasion, and metastasis. The 22 members of the ADP-ribosylation factor (ARF) and the >60 members of the rat sarcoma (RAS)-related in brain (RAB) families of small GTP-binding proteins (GTPases), which belong to the RAS superfamily, are master regulators of membrane trafficking pathways. ARF-like (ARL) subfamily members are involved in various processes, including vesicle budding and cargo selection. Moreover, ARFs regulate cytoskeleton organization and signal transduction. RABs are key regulators of all steps of membrane trafficking. Interestingly, the activity and/or expression of some of these proteins is found dysregulated in BC. Here, we review how the processes regulated by ARFs and RABs are subverted in BC, including secretion/exocytosis, endocytosis/recycling, autophagy/lysosome trafficking, cytoskeleton dynamics, integrin-mediated signaling, among others. Thus, we provide a comprehensive overview of the roles played by ARF and RAB family members, as well as their regulators in BC progression, aiming to lay the foundation for future research in this field. This research should focus on further dissecting the molecular mechanisms regulated by ARFs and RABs that are subverted in BC, and exploring their use as therapeutic targets or prognostic markers.

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Section: Arl8mentioning

confidence: 99%

Membrane trafficking alterations in breast cancer progression

Ferreira,

Castanheira,

Escrevente

et al. 2024

Front. Cell Dev. Biol.

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“…However, given that both Magic Red and Lysotracker label a range of acidic endo-lysosomal compartments, it should be noted that a spectrum of degradative organelles will be visualized with these probes. For simplicity, from this point on we will use the term "endolysosomes" to refer to those Lysotracker-positive organelles, which is also found in the wider literature (Keren-Kaplan et al, 2022;Roney et al, 2022;van Bommel et al, 2019).…”

Section: Lysotracker-positive Organelles In the Distal Axon Are Prote...mentioning

confidence: 99%

Efficient axonal transport of endolysosomes relies on the balanced ratio of microtubule tyrosination and detyrosination

Konietzny,

Han,

Popp

et al. 2024

Journal of Cell Science

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In neurons, the microtubule (MT) cytoskeleton forms the basis for long-distance protein transport from the cell body into and out of dendrites and axons. To maintain neuronal polarity, the axon initial segment (AIS) serves as a physical barrier, separating the axon from the somatodendritic compartment and acting as a filter for axonal cargo. Selective trafficking is further instructed by axonal enrichment of MT post-translational modifications, which affect MT dynamics and the activity of motor proteins. Here, we compared two knockout mouse lines lacking the respective enzymes for MT tyrosination and detyrosination and found that both knockouts led to a shortening of the AIS. Neurons from both lines also showed an increased immobile fraction of endolysosomes present in the axon, whereas mobile organelles displayed shortened run distances in the retrograde direction. Overall, our results highlight the importance of maintaining the balance of tyrosinated/detyrosinated MT for proper AIS length and axonal transport processes.

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RUFY3 links Arl8b and JIP4-Dynein complex to regulate lysosome size and positioning

et al. 2022

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The bidirectional movement of lysosomes on microtubule tracks regulates their whole-cell spatial arrangement. Arl8b, a small GTP-binding (G) protein, promotes lysosome anterograde trafficking mediated by kinesin-1. Herein, we report an Arl8b effector, RUFY3, which regulates the retrograde transport of lysosomes. We show that RUFY3 interacts with the JIP4-dynein-dynactin complex and facilitates Arl8b association with the retrograde motor complex. Accordingly, RUFY3 knockdown disrupts the positioning of Arl8b-positive endosomes and reduces Arl8b colocalization with Rab7-marked late endosomal compartments. Moreover, we find that RUFY3 regulates nutrient-dependent lysosome distribution, although autophagosome-lysosome fusion and autophagic cargo degradation are not impaired upon RUFY3 depletion. Interestingly, lysosome size is significantly reduced in RUFY3 depleted cells, which could be rescued by inhibition of the lysosome reformation regulatory factor PIKFYVE. These findings suggest a model in which the perinuclear cloud arrangement of lysosomes regulates both the positioning and size of these proteolytic compartments.

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RUFY3 and RUFY4 are ARL8 effectors that couple lysosomes to dynein-dynactin

Cited by 3 publications

References 92 publications

Membrane trafficking alterations in breast cancer progression

Membrane trafficking alterations in breast cancer progression

Efficient axonal transport of endolysosomes relies on the balanced ratio of microtubule tyrosination and detyrosination

RUFY3 links Arl8b and JIP4-Dynein complex to regulate lysosome size and positioning

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