UBL3 modification influences protein sorting to small extracellular vesicles

Hiroshi Ageta, Natsumi Ageta-Ishihara, Keisuke Hitachi, Ozge Karayel, Takanori Onouchi, Hisateru Yamaguchi, Tomoaki Kahyo, Ken Hatanaka, Koji Ikegami, Yusuke Yoshioka, Kenji Nakamura, Nobuyoshi Kosaka, Masashi Nakatani, Akiyoshi Uezumi, Tomihiko Ide, Yutaka Tsutsumi, Haruhiko Sugimura, Makoto Kinoshita, Takahiro Ochiya, Matthias Mann, Mitsutoshi Setou () and Kunihiro Tsuchida ()
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Hiroshi Ageta: Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho
Natsumi Ageta-Ishihara: Nagoya University Graduate School of Science
Keisuke Hitachi: Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho
Ozge Karayel: Max Planck Institute of Biochemistry
Takanori Onouchi: Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho
Hisateru Yamaguchi: Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho
Tomoaki Kahyo: Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minamiooya
Ken Hatanaka: Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minamiooya
Koji Ikegami: Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minamiooya
Yusuke Yoshioka: National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku
Kenji Nakamura: Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minamiooya
Nobuyoshi Kosaka: National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku
Masashi Nakatani: Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho
Akiyoshi Uezumi: Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho
Tomihiko Ide: Fujita Health University Joint research support promotion facility, 1-98 Dengakugakubo, Kutsukake-cho
Yutaka Tsutsumi: Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho
Haruhiko Sugimura: Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu
Makoto Kinoshita: Nagoya University Graduate School of Science
Takahiro Ochiya: National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku
Matthias Mann: Max Planck Institute of Biochemistry
Mitsutoshi Setou: Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minamiooya
Kunihiro Tsuchida: Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract Exosomes, a type of small extracellular vesicles (sEVs), derived from multivesicular bodies (MVBs), mediate cell-to-cell communication by transporting proteins, mRNAs, and miRNAs. However, the molecular mechanism by which proteins are sorted to sEVs is not fully understood. Here, we report that ubiquitin-like 3 (UBL3)/membrane-anchored Ub-fold protein (MUB) acts as a posttranslational modification (PTM) factor that regulates protein sorting to sEVs. We find that UBL3 modification is indispensable for sorting of UBL3 to MVBs and sEVs. We also observe a 60% reduction of total protein levels in sEVs purified from Ubl3-knockout mice compared with those from wild-type mice. By performing proteomics analysis, we find 1241 UBL3-interacting proteins, including Ras. We also show that UBL3 directly modifies Ras and oncogenic RasG12V mutant, and that UBL3 expression enhances sorting of RasG12V to sEVs via UBL3 modification. Collectively, these results indicate that PTM by UBL3 influences the sorting of proteins to sEVs.

Date: 2018
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DOI: 10.1038/s41467-018-06197-y

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