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

研究成果: Article › 査読

17 被引用数 (Scopus)

抄録

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.

本文言語	English
論文番号	3936
ジャーナル	Nature communications
巻	9
号	1
DOI	https://doi.org/10.1038/s41467-018-06197-y
出版ステータス	Published - 01-12-2018

All Science Journal Classification (ASJC) codes

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

文献へのアクセス

10.1038/s41467-018-06197-y

フィンガープリント「UBL3 modification influences protein sorting to small extracellular vesicles」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル

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, 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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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",

note = "Funding Information: The authors thank Showbu Sato, T. Hino, and R. Migishima for the generation of the Ubl3 KO mice; Y. Oda and M. Ambai for the phylogenetic tree analysis; M. Kono, G. Niimi, N. Yamamoto, and K. Taniguchi for suggestions and technical support in electron microscope analysis; K. Otsu, Saori Sato, Y. Kato, and N. Kawamura for technical assistance; S. Kamijo, M. Matsuo, and S. Nagao for maintenance of the UBL3 KO mice; A. Yamaguchi for genotyping the Ubl3 KO mice; and S. Ono and A. Kato for suggestions and discussion. This work was initiated while H.A. was a research scientist at MITILS, and sEV analyses were mainly performed at FHU. This work was partly supported by JSPS KAKENHI (22700346, 26640084, JP16H06280, 17H05945, 18K07209, and 16K08599); an Intramural Research Grant (26-8 and 29-4) for Neurological and Psychiatric Disorders of NCNP; the Ministry of Education, Culture, Sports, Science and Technology (Grant No.15H05898B1); CREST from Japan Agency for Medical Research and Development; AMED (Grant No.921910520); Innovative Areas-Resource and technical support platforms for promoting research {\textquoteleft}Advanced Bioimaging Support{\textquoteright}; {\textquoteleft}Fluorescence Live imaging{\textquoteright} of the Ministry of Education, Culture, Sports, Science and Technology; and the Program for Strategic Research Foundation at Private Universities.",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-06197-y",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

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.

研究成果: Article › 査読

TY - JOUR

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

N1 - Funding Information: The authors thank Showbu Sato, T. Hino, and R. Migishima for the generation of the Ubl3 KO mice; Y. Oda and M. Ambai for the phylogenetic tree analysis; M. Kono, G. Niimi, N. Yamamoto, and K. Taniguchi for suggestions and technical support in electron microscope analysis; K. Otsu, Saori Sato, Y. Kato, and N. Kawamura for technical assistance; S. Kamijo, M. Matsuo, and S. Nagao for maintenance of the UBL3 KO mice; A. Yamaguchi for genotyping the Ubl3 KO mice; and S. Ono and A. Kato for suggestions and discussion. This work was initiated while H.A. was a research scientist at MITILS, and sEV analyses were mainly performed at FHU. This work was partly supported by JSPS KAKENHI (22700346, 26640084, JP16H06280, 17H05945, 18K07209, and 16K08599); an Intramural Research Grant (26-8 and 29-4) for Neurological and Psychiatric Disorders of NCNP; the Ministry of Education, Culture, Sports, Science and Technology (Grant No.15H05898B1); CREST from Japan Agency for Medical Research and Development; AMED (Grant No.921910520); Innovative Areas-Resource and technical support platforms for promoting research ‘Advanced Bioimaging Support’; ‘Fluorescence Live imaging’ of the Ministry of Education, Culture, Sports, Science and Technology; and the Program for Strategic Research Foundation at Private Universities.

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.

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