The Ragulator complex and lysosomal calcium release are crucial for cell migration

Tatsunori Jo; Kohei Tsujimoto; Takeshi Nakatani; Daiki Nagira; Yutaka Muto; Takehiro Hirayama; Hachiro Konaka; Masato Okada; Hyota Takamatsu; Atsushi Kumanogoh

doi:10.26508/lsa.202403015

The Ragulator complex and lysosomal calcium release are crucial for cell migration

Life Sci Alliance. 2025 Jun 10;8(8):e202403015. doi: 10.26508/lsa.202403015. Print 2025 Aug.

Authors

Tatsunori Jo^{1

2

3}, Kohei Tsujimoto^{1

2

3}, Takeshi Nakatani^{1

4}, Daiki Nagira¹, Yutaka Muto^{1

2

3}, Takehiro Hirayama^{1

2

3}, Hachiro Konaka^{1

5}, Masato Okada⁶, Hyota Takamatsu^{7

8}, Atsushi Kumanogoh^{9

2

3

10

11

12

13}

Affiliations

¹ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
² Department of Immunopathology, WPI, Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan.
³ The Japan Science and Technology - Core Research for Evolutional Science and Technology (JST-CREST), Osaka University, Osaka, Japan.
⁴ Department of Respiratory Medicine, Osaka Keisatsu Hospital, Osaka, Japan.
⁵ Department of Internal Medicine, Nippon Life Hospital, Osaka, Japan.
⁶ Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
⁷ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan thyota@imed3.med.osaka-u.ac.jp.
⁸ Department of Clinical Research Center, National Hospital Organization Osaka Minami Medical Center, Osaka, Japan.
⁹ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan kumanogo@imed3.med.osaka-u.ac.jp.
¹⁰ Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
¹¹ Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Osaka University, Osaka, Japan.
¹² Center for Advanced Modalities and DDS (CAMaD), Osaka University, Osaka, Japan.
¹³ Center for Infectious Disease for Education and Research (CiDER), Osaka University, Osaka, Japan.

Abstract

Immune cells migrate via actomyosin contractility mediated by myosin IIA activation, wherein the lysosomal Ragulator complex-MPRIP interaction is crucial. However, the precise mechanism underlying lysosome-mediated myosin IIA activation has not been elucidated. Here, we found that calcium efflux from the lysosomal TRPML1 channel promotes leukocyte trafficking by enhancing the interaction between the Ragulator complex and MPRIP. Disrupting the lysosome-anchoring site of Lamtor1 impaired the localization of the Ragulator complex to lysosomes, diminishing the TRPML1-mediated leukocyte migration and interaction between Lamtor1 and MPRIP. Furthermore, ouabain, a cardiac glycoside, dissociated Lamtor1 from lysosomes, inhibiting the interaction between the Ragulator complex and myosin IIA activation, thereby suppressing cell migration. Therapeutically, ouabain ameliorated the severity of MSU-induced gouty arthritis and LPS-induced lung injury in mice by inhibiting leukocyte infiltration. Overall, lysosomes facilitate the interaction between the Ragulator complex and MPRIP by supplying calcium ions through TRPML1 channels, thereby activating myosin IIA and promoting leukocyte migration.

MeSH terms

Adaptor Proteins, Signal Transducing* / metabolism
Animals
Calcium* / metabolism
Cell Movement* / drug effects
Cell Movement* / physiology
Humans
Leukocytes / metabolism
Lysosomes* / metabolism
Male
Mice
Mice, Inbred C57BL
Nonmuscle Myosin Type IIA / metabolism
Transient Receptor Potential Channels / metabolism

Substances

Calcium
Nonmuscle Myosin Type IIA
Transient Receptor Potential Channels
Adaptor Proteins, Signal Transducing