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UBL3 modification influences protein sorting to small extracellular vesicles

Author

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  • Hiroshi Ageta

    (Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho
    Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minamiooya)

  • 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
    Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu)

  • Ken Hatanaka

    (Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minamiooya
    Discovery, Medicine Creation, Neurology Business Group, Eisai Co., Ltd., 1-3 Tokodai 5-Chome)

  • Koji Ikegami

    (Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minamiooya
    Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu
    Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima
    JST, PRESTO, 4-1-8 Honcho, Kawaguchi)

  • Yusuke Yoshioka

    (National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku
    Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku)

  • Kenji Nakamura

    (Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minamiooya
    Nitobebunka College, Department of Clinical Laboratory Sciences, 43-16 Nakano 3-Chome, Nakanoku)

  • Nobuyoshi Kosaka

    (National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku
    Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-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
    Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-ku)

  • Matthias Mann

    (Max Planck Institute of Biochemistry)

  • Mitsutoshi Setou

    (Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minamiooya
    Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu
    Preeminent Medical Photonics, Education & Research Center, 1-20-1 Handayama, Higashi-ku, Hamamatsu
    The University of Hong Kong, 6/F, William MW Mong Block 21 Sassoon Road, Pokfulam)

  • Kunihiro Tsuchida

    (Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho)

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.

Suggested Citation

  • Hiroshi Ageta & Natsumi Ageta-Ishihara & Keisuke Hitachi & Ozge Karayel & Takanori Onouchi & Hisateru Yamaguchi & Tomoaki Kahyo & Ken Hatanaka & Koji Ikegami & Yusuke Yoshioka & Kenji Nakamura & Nobuy, 2018. "UBL3 modification influences protein sorting to small extracellular vesicles," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06197-y
    DOI: 10.1038/s41467-018-06197-y
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