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RUFY3 和 RUFY4 是 ARL8 的效应物，可促进内溶酶体与动力蛋白-动力蛋白激活蛋白复合物的连接。

RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin.

机构信息

Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

出版信息

Nat Commun. 2022 Mar 21;13(1):1506. doi: 10.1038/s41467-022-28952-y.

DOI:10.1038/s41467-022-28952-y
PMID:35314674
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8938451/
Abstract

The small GTPase ARL8 associates with endolysosomes, leading to the recruitment of several effectors that couple endolysosomes to kinesins for anterograde transport along microtubules, and to tethering factors for eventual fusion with other organelles. Herein we report the identification of the RUN- and FYVE-domain-containing proteins RUFY3 and RUFY4 as ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin for retrograde transport along microtubules. Using various methodologies, we find that RUFY3 and RUFY4 interact with both GTP-bound ARL8 and dynein-dynactin. In addition, we show that RUFY3 and RUFY4 promote concentration of endolysosomes in the juxtanuclear area of non-neuronal cells, and drive redistribution of endolysosomes from the axon to the soma in hippocampal neurons. The function of RUFY3 in retrograde transport contributes to the juxtanuclear redistribution of endolysosomes upon cytosol alkalinization. These studies thus identify RUFY3 and RUFY4 as ARL8-dependent, dynein-dynactin adaptors or regulators, and highlight the role of ARL8 in the control of both anterograde and retrograde endolysosome transport.

摘要

小分子 GTP 酶 ARL8 与内溶酶体结合，导致招募几个效应因子，将内溶酶体与动力蛋白偶联，沿微管进行正向运输，并与锚定因子结合，最终与其他细胞器融合。在此，我们报告了 RUN 和 FYVE 结构域蛋白 RUFY3 和 RUFY4 作为 ARL8 效应因子的鉴定，它们促进内溶酶体与动力蛋白-动力蛋白复合物的偶联，用于沿微管进行逆行运输。使用各种方法，我们发现 RUFY3 和 RUFY4 与 GTP 结合的 ARL8 和动力蛋白-动力蛋白复合物都相互作用。此外，我们还表明 RUFY3 和 RUFY4 促进非神经元细胞中核周区域内溶酶体的浓缩，并在海马神经元中驱动内溶酶体从轴突重新分布到胞体。RUFY3 在逆行运输中的功能有助于细胞质碱化时内溶酶体在核周的重新分布。这些研究因此确定了 RUFY3 和 RUFY4 是 ARL8 依赖性、动力蛋白-动力蛋白复合物的衔接子或调节剂，并强调了 ARL8 在控制内溶酶体正向和逆行运输中的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/4951e4c8807b/41467_2022_28952_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/6bdb42099a7b/41467_2022_28952_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/a63240865799/41467_2022_28952_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/05a2bafa5d43/41467_2022_28952_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/a166e6134317/41467_2022_28952_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/1e4b8def67ef/41467_2022_28952_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/a7aba188beb6/41467_2022_28952_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/3863c729dd12/41467_2022_28952_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/c7c7710863f4/41467_2022_28952_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/4951e4c8807b/41467_2022_28952_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/6bdb42099a7b/41467_2022_28952_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/a63240865799/41467_2022_28952_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/05a2bafa5d43/41467_2022_28952_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/a166e6134317/41467_2022_28952_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/1e4b8def67ef/41467_2022_28952_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/a7aba188beb6/41467_2022_28952_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/3863c729dd12/41467_2022_28952_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/c7c7710863f4/41467_2022_28952_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd23/8938451/4951e4c8807b/41467_2022_28952_Fig9_HTML.jpg

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本文引用的文献

[1]
RUFY3 links Arl8b and JIP4-Dynein complex to regulate lysosome size and positioning.

Nat Commun. 2022-3-21

[2]
SNX19 restricts endolysosome motility through contacts with the endoplasmic reticulum.

Nat Commun. 2021-7-27

[3]
Sequential dynein effectors regulate axonal autophagosome motility in a maturation-dependent pathway.

J Cell Biol. 2021-7-5

[4]
Rab2 drives axonal transport of dense core vesicles and lysosomal organelles.

Cell Rep. 2021-4-13

[5]
Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons.

Mol Biol Cell. 2021-5-15

[6]
A septin GTPase scaffold of dynein-dynactin motors triggers retrograde lysosome transport.

J Cell Biol. 2021-2-1

[7]
ARL8 Relieves SKIP Autoinhibition to Enable Coupling of Lysosomes to Kinesin-1.

Curr Biol. 2021-2-8

[8]
β-Coronaviruses Use Lysosomes for Egress Instead of the Biosynthetic Secretory Pathway.

Cell. 2020-10-27

[9]
The GTPase Arl8B Plays a Principle Role in the Positioning of Interstitial Axon Branches by Spatially Controlling Autophagosome and Lysosome Location.

J Neurosci. 2020-10-14

[10]
The RUFYs, a Family of Effector Proteins Involved in Intracellular Trafficking and Cytoskeleton Dynamics.

Front Cell Dev Biol. 2020-8-11

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