The Rubicon-WIPI axis regulates exosome biogenesis during ageing

Kyosuke Yanagawa^{1

2}, Akiko Kuma^{1

3}, Maho Hamasaki^{1

4}, Shunbun Kita^{5

6}, Tadashi Yamamuro⁷, Kohei Nishino⁸, Shuhei Nakamura^{1

4

9

10}, Hiroko Omori¹¹, Tatsuya Kaminishi^{1

12}, Satoshi Oikawa^{7

13}, Yoshio Kato¹⁴, Ryuya Edahiro^{15

16}, Ryosuke Kawagoe¹⁷, Takako Taniguchi¹⁷, Yoko Tanaka¹⁸, Takayuki Shima^{1

10}, Keisuke Tabata^{1

4}, Miki Iwatani¹, Nao Bekku¹, Rikinari Hanayama^{19

20}, Yukinori Okada^{15

21

22

23

24}, Takayuki Akimoto²⁵, Hidetaka Kosako⁸, Akiko Takahashi¹⁸, Iichiro Shimomura⁵, Yasushi Sakata², Tamotsu Yoshimori^{26

27

28

29}

Affiliations

¹ Department of Genetics, Graduate School of Medicine, Osaka University, Suita, Japan.
² Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Japan.
³ Health Promotion System Science, Graduate School of Medicine, Osaka University, Suita, Japan.
⁴ Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan.
⁵ Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan.
⁶ Tokyo New Drug Research Laboratories, Pharmaceutical Business Unit, Kowa Company, Higashimurayama, Japan.
⁷ Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁸ Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
⁹ Institute for Advanced Co-Creation Studies, Osaka University, Suita, Japan.
¹⁰ Department of Biochemistry, Nara Medical University, Kashihara, Japan.
¹¹ Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
¹² Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan.
¹³ Waseda Institute for Sport Sciences, Waseda University, Tokorozawa, Japan.
¹⁴ Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan.
¹⁵ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
¹⁶ Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.
¹⁷ i2i-Labo, Yokohama Research Center, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Yokohama, Japan.
¹⁸ Division of Cellular Senescence, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
¹⁹ Department of Immunology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
²⁰ WPI Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.
²¹ Department of Genome Informatics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
²² Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
²³ Laboratory of Statistical Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan.
²⁴ WPI Premium Research Institute for Human Metaverse Medicine, Osaka University, Suita, Japan.
²⁵ Laboratory of Muscle Biology, Faculty of Sport Sciences, Waseda University, Tokorozawa, Japan.
²⁶ Department of Genetics, Graduate School of Medicine, Osaka University, Suita, Japan. tamotsu.yoshimori@gmail.com.
²⁷ Health Promotion System Science, Graduate School of Medicine, Osaka University, Suita, Japan. tamotsu.yoshimori@gmail.com.
²⁸ Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan. tamotsu.yoshimori@gmail.com.
²⁹ Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan. tamotsu.yoshimori@gmail.com.

PMID: 39174742
DOI: 10.1038/s41556-024-01481-0

The Rubicon-WIPI axis regulates exosome biogenesis during ageing

Kyosuke Yanagawa et al. Nat Cell Biol. 2024 Sep.

. 2024 Sep;26(9):1558-1570.

doi: 10.1038/s41556-024-01481-0. Epub 2024 Aug 22.

Authors

Affiliations

¹ Department of Genetics, Graduate School of Medicine, Osaka University, Suita, Japan.
² Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Japan.
³ Health Promotion System Science, Graduate School of Medicine, Osaka University, Suita, Japan.
⁴ Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan.
⁵ Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan.
⁶ Tokyo New Drug Research Laboratories, Pharmaceutical Business Unit, Kowa Company, Higashimurayama, Japan.
⁷ Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁸ Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
⁹ Institute for Advanced Co-Creation Studies, Osaka University, Suita, Japan.
¹⁰ Department of Biochemistry, Nara Medical University, Kashihara, Japan.
¹¹ Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
¹² Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan.
¹³ Waseda Institute for Sport Sciences, Waseda University, Tokorozawa, Japan.
¹⁴ Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan.
¹⁵ Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
¹⁶ Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.
¹⁷ i2i-Labo, Yokohama Research Center, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Yokohama, Japan.
¹⁸ Division of Cellular Senescence, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
¹⁹ Department of Immunology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
²⁰ WPI Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.
²¹ Department of Genome Informatics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
²² Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
²³ Laboratory of Statistical Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan.
²⁴ WPI Premium Research Institute for Human Metaverse Medicine, Osaka University, Suita, Japan.
²⁵ Laboratory of Muscle Biology, Faculty of Sport Sciences, Waseda University, Tokorozawa, Japan.
²⁶ Department of Genetics, Graduate School of Medicine, Osaka University, Suita, Japan. tamotsu.yoshimori@gmail.com.
²⁷ Health Promotion System Science, Graduate School of Medicine, Osaka University, Suita, Japan. tamotsu.yoshimori@gmail.com.
²⁸ Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan. tamotsu.yoshimori@gmail.com.
²⁹ Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan. tamotsu.yoshimori@gmail.com.

PMID: 39174742
DOI: 10.1038/s41556-024-01481-0

Abstract

Cells release intraluminal vesicles in multivesicular bodies as exosomes to communicate with other cells. Although recent studies suggest an intimate link between exosome biogenesis and autophagy, the detailed mechanism is not fully understood. Here we employed comprehensive RNA interference screening for autophagy-related factors and discovered that Rubicon, a negative regulator of autophagy, is essential for exosome release. Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Interactome analysis of WIPI2d identified the ESCRT components that are required for intraluminal vesicle formation. Notably, we found that Rubicon is required for an age-dependent increase of exosome release in mice. In addition, small RNA sequencing of serum exosomes revealed that Rubicon determines the fate of exosomal microRNAs associated with cellular senescence and longevity pathways. Taken together, our current results suggest that the Rubicon-WIPI axis functions as a key regulator of exosome biogenesis and is responsible for age-dependent changes in exosome quantity and quality.

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References

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The Rubicon-WIPI axis regulates exosome biogenesis during ageing

Affiliations

The Rubicon-WIPI axis regulates exosome biogenesis during ageing

Authors

Affiliations

Abstract

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources