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

Author

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  • Gaurav Kumar

    (CSIR-Institute of Microbial Technology (IMTECH))

  • Prateek Chawla

    (Indian Institute of Science Education and Research (IISER))

  • Neha Dhiman

    (Indian Institute of Science Education and Research (IISER))

  • Sanya Chadha

    (CSIR-Institute of Microbial Technology (IMTECH))

  • Sheetal Sharma

    (CSIR-Institute of Microbial Technology (IMTECH))

  • Kanupriya Sethi

    (CSIR-Institute of Microbial Technology (IMTECH))

  • Mahak Sharma

    (Indian Institute of Science Education and Research (IISER))

  • Amit Tuli

    (CSIR-Institute of Microbial Technology (IMTECH))

Abstract

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.

Suggested Citation

  • Gaurav Kumar & Prateek Chawla & Neha Dhiman & Sanya Chadha & Sheetal Sharma & Kanupriya Sethi & Mahak Sharma & Amit Tuli, 2022. "RUFY3 links Arl8b and JIP4-Dynein complex to regulate lysosome size and positioning," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29077-y
    DOI: 10.1038/s41467-022-29077-y
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    References listed on IDEAS

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    1. Aysegul Sapmaz & Ilana Berlin & Erik Bos & Ruud H. Wijdeven & Hans Janssen & Rebecca Konietzny & Jimmy J. Akkermans & Ayse E. Erson-Bensan & Roman I. Koning & Benedikt M. Kessler & Jacques Neefjes & H, 2019. "USP32 regulates late endosomal transport and recycling through deubiquitylation of Rab7," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    2. Rose Willett & José A. Martina & James P. Zewe & Rachel Wills & Gerald R. V. Hammond & Rosa Puertollano, 2017. "TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes," Nature Communications, Nature, vol. 8(1), pages 1-17, December.
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    1. Eutteum Jeong & Rose Willett & Alberto Rissone & Martina Spina & Rosa Puertollano, 2024. "TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Agnieszka A. Kendrick & Jenna R. Christensen, 2022. "Bidirectional lysosome transport: a balancing act between ARL8 effectors," Nature Communications, Nature, vol. 13(1), pages 1-3, December.
    3. Rahul Kumar & Maleeha Khan & Vincent Francis & Adriana Aguila & Gopinath Kulasekaran & Emily Banks & Peter S. McPherson, 2024. "DENND6A links Arl8b to a Rab34/RILP/dynein complex, regulating lysosomal positioning and autophagy," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. Tal Keren-Kaplan & Amra Sarić & Saikat Ghosh & Chad D. Williamson & Rui Jia & Yan Li & Juan S. Bonifacino, 2022. "RUFY3 and RUFY4 are ARL8 effectors that promote coupling of endolysosomes to dynein-dynactin," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    5. Kshitiz Walia & Abhishek Sharma & Sankalita Paul & Priya Chouhan & Gaurav Kumar & Rajesh Ringe & Mahak Sharma & Amit Tuli, 2024. "SARS-CoV-2 virulence factor ORF3a blocks lysosome function by modulating TBC1D5-dependent Rab7 GTPase cycle," Nature Communications, Nature, vol. 15(1), pages 1-24, December.

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