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; Kunihiro Tsuchida

doi:10.1038/s41467-018-06197-y

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

20 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 language	English
Journal	Nature Communications
Volume	9
Issue number	1
Pages (from-to)	3936
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-018-06197-y
Publication status	Published - 1 Dec 2018
Externally published	Yes

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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., ... Tsuchida, K. (2018). UBL3 modification influences protein sorting to small extracellular vesicles. Nature Communications, 9(1), 3936. https://doi.org/10.1038/s41467-018-06197-y

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, pp. 3936. https://doi.org/10.1038/s41467-018-06197-y

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title = "UBL3 modification influences protein sorting to small extracellular vesicles",

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.",

author = "Hiroshi Ageta and Natsumi Ageta-Ishihara and Keisuke Hitachi and Ozge Karayel and Takanori Onouchi and Hisateru Yamaguchi and Tomoaki Kahyo and Ken Hatanaka and Koji Ikegami and Yusuke Yoshioka and Kenji Nakamura and Nobuyoshi Kosaka and Masashi Nakatani and Akiyoshi Uezumi and Tomihiko Ide and Yutaka Tsutsumi and Haruhiko Sugimura and Makoto Kinoshita and Takahiro Ochiya and Matthias Mann and Mitsutoshi Setou and Kunihiro Tsuchida",

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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.

AB - 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.

U2 - 10.1038/s41467-018-06197-y

DO - 10.1038/s41467-018-06197-y

M3 - Journal article

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SN - 2041-1723

VL - 9

SP - 3936

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

UBL3 modification influences protein sorting to small extracellular vesicles

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