The RUFYs, a Family of Effector Proteins Involved in Intracellular Trafficking and Cytoskeleton Dynamics

Char, Rémy; Pierre, Philippe

doi:10.3389/fcell.2020.00779

Cited by 23 publications

(40 citation statements)

References 168 publications

(235 reference statements)

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“…1d). RUFY3 is one of 4 members of the RUFY family of proteins in humans (Char and Pierre, 2020). These proteins comprise, in N-to C-terminal direction, RUN, coiled-coil (CC) and FYVE domains joined by disordered sequences (Fig.…”

Section: Identification Of Rufy3 and Rufy4 As Arl8 Effectorsmentioning

confidence: 99%

“…1d). RUFY3, in particular, has two CC domains (CC1 and CC2) and exists as 6 spliceforms, two of which are the 620-amino-acid RUFY3.1 (transcript variant 1) (NM_001037442) (also known as RUFY3XL, (Char and Pierre, 2020) and the 469amino-acid RUFY3.2 (transcript variant 2) (NM_014961) (Fig. 1d).…”

Section: Identification Of Rufy3 and Rufy4 As Arl8 Effectorsmentioning

confidence: 99%

“…Herein we report the results of a search for additional ARL8 effectors using MitoID (Gillingham et al, 2019), a method involving proximity biotinylation with mitochondriallytargeted forms of human ARL8A and ARL8B, followed by isolation of biotinylated proteins and mass spectrometry. Using this method, we identify the "RUN and FYVE domain-containing" proteins RUFY3 and RUFY4 (Char and Pierre, 2020) as novel ARL8 effectors. We find that ARL8 mediates recruitment of RUFY3/4 to lysosomes, promoting lysosome redistribution toward the juxtanuclear area of the cell.…”

Section: Introductionmentioning

confidence: 99%

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

Keren-Kaplan¹,

Sarić²,

Ghosh³

et al. 2021

Preprint

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The small GTPase ARL8 associates with lysosomes and recruits several effectors that mediate coupling to kinesins for anterograde transport, as well as tethering for eventual fusion with other organelles. Herein we report the identification of the “RUN- and FYVE-domain-containing” proteins RUFY3 and RUFY4 as novel ARL8 effectors that couple lysosomes to dynein-dynactin for retrograde transport. Using various biochemical approaches, we find that RUFY3/4 interact with both GTP-bound ARL8 and dynein-dynactin. In addition, we show that RUFY3/4 are both necessary and sufficient for concentration of lysosomes in the juxtanuclear area of the cell. RUFY3/4 also promote retrograde transport of lysosomes in the axon of hippocampal neurons. The function of RUFY3/4 in retrograde transport is required for juxtanuclear redistribution of lysosomes upon serum starvation or cytoplasmic alkalinization, and may underlie the reported roles of RUFY3/4 in axon development/degeneration, cancer and immunity. These studies thus establish RUFY3/4 as novel ARL8-dependent, dynein-dynactin adaptors, and highlight the role of ARL8 in the regulation of both anterograde and retrograde lysosome transport.

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Section: Identification Of Rufy3 and Rufy4 As Arl8 Effectorsmentioning

confidence: 99%

Section: Identification Of Rufy3 and Rufy4 As Arl8 Effectorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Keren-Kaplan¹,

Sarić²,

Ghosh³

et al. 2021

Preprint

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“…Transcript variant 1 (hereafter referred to as RUFY3) is the longest transcript synthesized from the RUFY3 gene, which encodes for six alternatively spliced variants. Variant 2 of RUFY3 (NM_014961.5, NP_055776.1; 469 amino acids in length) is the only RUFY3 isoform that is functionally characterized and regulate polarity and axon growth in neurons and migration and invasion of cancer cells (Char and Pierre, 2020;Honda et al, 2017;Kitagishi and Matsuda, 2013;Mori et al, 2007;Wang et al, 2015;Wei et al, 2014;Xie et al, 2017).…”

Section: Rufy3 Is An Arl8b Effector That Localizes To Lysosomesmentioning

confidence: 99%

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

Kumar¹,

Chawla²,

Chadha³

et al. 2021

Preprint

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The whole-cell scale spatial organization of lysosomes is regulated by their bidirectional motility on microtubule tracks. Small GTP-binding (G) protein, Arl8b, stimulates the anterograde transport of lysosomes by recruiting adaptor protein SKIP (also known as PLEKHM2), which in turn couples the microtubule motor kinesin-1. Here, we have identified an Arl8b effector, RUN and FYVE domain-containing protein family member 3, RUFY3, which drives the retrograde transport of lysosomes. Artificial targeting of RUFY3 to the surface of mitochondria was sufficient to drive their perinuclear positioning. We find that RUFY3 interacts with the JIP4-Dynein-Dynactin complex and mediates Arl8b association with the retrograde motor complex. The mobile fraction of the total lysosomes per cell was significantly enhanced upon RUFY3 depletion, suggesting that RUFY3 maintains the lysosomes clustering within the perinuclear cloud. Expectedly, RUFY3 knockdown disrupted the perinuclear positioning of lysosomes upon nutrient starvation and/or serum depletion, although lysosome continued to undergo fusion with autophagosomes. Interestingly, lysosome fission events were more frequent in RUFY3-depleted cells and accordingly, there was a striking reduction in lysosome size, an effect that was also observed in dynein and JIP4 depleted cells. These findings indicate that the dynein-dependent “perinuclear cloud” arrangement of lysosomes also regulates the size of these proteolytic compartments and, likely, their cellular roles.

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“…RUN and FYVE domain-containing proteins (RUFYs), consisting of an N-terminal RUN domain and a Phosphatidylinositol 3-phosphate (PI3P)-interacting C-terminal FYVE domain, have taken center stage in the oncology eld [10]. RUFY1 is proved to interact with podocalyxin-like (PODXL) protein, an iron exchanger regulatory factor in the membrane protein complex associated with poor prognosis of different cancers [11,12].…”

Section: Introductionmentioning

confidence: 99%

As a Newly-Discovered Component in Tumor Microenvironment RUFY4 Participates in Regulation of T cell via Cytokine-Interaction and Predicts Prognosis and Immunotherapy Responsiveness of Clear Cell Renal Carcinoma Patients

Miao¹,

Shi²,

Zhang³

et al. 2020

Preprint

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Background: clear cell renal cell carcinoma (ccRCC) is one of the most lethal kinds of malignancies in urinary system and the existing immunotherapy have not achieved satisfactory outcomes. Therefore, this study aims to establish a brand-new gene signature for immune-infiltration and clinical outcome (overall survival and immunotherapy responsiveness) of patients with ccRCC. Methods: Based on RNA sequencing data and clinical information in the Cancer Genome Atlas Project (TCGA) database, we investigated proportions of immune cells in 611 samples by an online tool CIBERSORTx. Multivariate survival analysis was used to determine crucial survival-associated immune cells and immune-infiltration-related genes (IIRGs). Next ROC analysis was carried on to evaluate the ability of IIRGs to distinguish patients and functional enrichment analysis were implemented to explore potential interaction network between immune cells and IIRGs. Results: T cells follicular helper (TFHs) and T cells regulatory (Tregs) were highly infiltrated in the tumor microenvironment and their abundance ratios were independent prognostic factors for overall survival. Among IIRGs of TFHs and TREGs, RUFY4 was found to be highly activated in tumor microenvironment and its co-expression network was enriched in regulation of T cells via cytokine-cytokine receptor interactions.Conclusion: These two cells and RUFY4, considered prognostic biomarkers and immunotherapeutic predictors of ccRCC patients, might also simultaneously affect the regulatory network in tumor microenvironment (TME) through cytokine interactions.

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The RUFYs, a Family of Effector Proteins Involved in Intracellular Trafficking and Cytoskeleton Dynamics

Cited by 23 publications

References 168 publications

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

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

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

As a Newly-Discovered Component in Tumor Microenvironment RUFY4 Participates in Regulation of T cell via Cytokine-Interaction and Predicts Prognosis and Immunotherapy Responsiveness of Clear Cell Renal Carcinoma Patients

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