The Rubicon-WIPI axis regulates exosome biogenesis during aging

Kyosuke Yanagawa; Akiko Kuma; Maho Hamasaki; Shunbun Kita; Tadashi Yamamuro; Kohei Nishino; Shuhei Nakamura; Hiroko Omori; Tatsuya Kaminishi; Satoshi Oikawa; Yoshio Kato; Ryuya Edahiro; Ryosuke Kawagoe; Takako Taniguchi; Yôko Tanaka; Takayuki Shima; Keisuke Tabata; Miki Iwatani; Nao Bekku; Rikinari Hanayama; Yukinori Okada; Takayuki Akimoto; Hidetaka Kosako; Akiko Takahashi; Iichiro Shimomura; Yasushi Sakata; Tamotsu Yoshimori

doi:10.1038/s41556-024-01481-0

Cell BiologyNature Cell BiologyAug 22, 2024

Peer-reviewed journal article

The Rubicon-WIPI axis regulates exosome biogenesis during aging

Kyosuke Yanagawa iD, Akiko Kuma iD, Maho Hamasaki iD, Shunbun Kita iD, Tadashi Yamamuro iD, Kohei Nishino iD, Shuhei Nakamura iD, Hiroko Omori, Tatsuya Kaminishi iD, Satoshi Oikawa iD, Yoshio Kato iD, Ryuya Edahiro iD, Ryosuke Kawagoe, Takako Taniguchi, Yôko Tanaka iD, Takayuki Shima iD, Keisuke Tabata iD, Miki Iwatani, Nao Bekku, Rikinari Hanayama iD, Yukinori Okada iD, Takayuki Akimoto iD, Hidetaka Kosako iD, Akiko Takahashi iD, Iichiro Shimomura iD, , Tamotsu Yoshimori iD

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Abstract

Cells release intraluminal vesicles (ILVs) 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 RNAi 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 ILV 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 the age-dependent changes in exosome quantity and quality.