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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U2 - 10.1038/s41467-018-06197-y
DO - 10.1038/s41467-018-06197-y
M3 - Article
C2 - 30258067
AN - SCOPUS:85054090181
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3936
ER -