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 MannMitsutoshi Setou, Kunihiro Tsuchida

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Article number3936
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 01-12-2018

Fingerprint

Protein Transport
Ubiquitin
classifying
Sorting
proteins
Proteins
Multivesicular Bodies
Post Translational Protein Processing
knockout mice
Exosomes
ras Proteins
Extracellular Vesicles
cells
mice
MicroRNAs
Knockout Mice
Cell Communication
Proteomics
communication
membranes

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Ageta, Hiroshi ; Ageta-Ishihara, Natsumi ; Hitachi, Keisuke ; Karayel, Ozge ; Onouchi, Takanori ; Yamaguchi, Hisateru ; Kahyo, Tomoaki ; Hatanaka, Ken ; Ikegami, Koji ; Yoshioka, Yusuke ; Nakamura, Kenji ; Kosaka, Nobuyoshi ; Nakatani, Masashi ; Uezumi, Akiyoshi ; Ide, Tomihiko ; Tsutsumi, Yutaka ; Sugimura, Haruhiko ; Kinoshita, Makoto ; Ochiya, Takahiro ; Mann, Matthias ; Setou, Mitsutoshi ; Tsuchida, Kunihiro. / UBL3 modification influences protein sorting to small extracellular vesicles. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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Ageta, H, Ageta-Ishihara, N, Hitachi, K, Karayel, O, Onouchi, T, Yamaguchi, H, Kahyo, T, Hatanaka, K, Ikegami, K, Yoshioka, Y, Nakamura, K, Kosaka, N, Nakatani, M, Uezumi, A, Ide, T, Tsutsumi, Y, Sugimura, H, Kinoshita, M, Ochiya, T, Mann, M, Setou, M & Tsuchida, K 2018, 'UBL3 modification influences protein sorting to small extracellular vesicles', Nature Communications, vol. 9, no. 1, 3936. https://doi.org/10.1038/s41467-018-06197-y

UBL3 modification influences protein sorting to small extracellular vesicles. / Ageta, Hiroshi; Ageta-Ishihara, Natsumi; Hitachi, Keisuke; Karayel, Ozge; Onouchi, Takanori; Yamaguchi, Hisateru; Kahyo, Tomoaki; Hatanaka, Ken; Ikegami, Koji; Yoshioka, Yusuke; Nakamura, Kenji; Kosaka, Nobuyoshi; Nakatani, Masashi; Uezumi, Akiyoshi; Ide, Tomihiko; Tsutsumi, Yutaka; Sugimura, Haruhiko; Kinoshita, Makoto; Ochiya, Takahiro; Mann, Matthias; Setou, Mitsutoshi; Tsuchida, Kunihiro.

In: Nature Communications, Vol. 9, No. 1, 3936, 01.12.2018.

Research output: Contribution to journalArticle

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T1 - UBL3 modification influences protein sorting to small extracellular vesicles

AU - Ageta, Hiroshi

AU - Ageta-Ishihara, Natsumi

AU - Hitachi, Keisuke

AU - Karayel, Ozge

AU - Onouchi, Takanori

AU - Yamaguchi, Hisateru

AU - Kahyo, Tomoaki

AU - Hatanaka, Ken

AU - Ikegami, Koji

AU - Yoshioka, Yusuke

AU - Nakamura, Kenji

AU - Kosaka, Nobuyoshi

AU - Nakatani, Masashi

AU - Uezumi, Akiyoshi

AU - Ide, Tomihiko

AU - Tsutsumi, Yutaka

AU - Sugimura, Haruhiko

AU - Kinoshita, Makoto

AU - Ochiya, Takahiro

AU - Mann, Matthias

AU - Setou, Mitsutoshi

AU - Tsuchida, Kunihiro

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

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