TY - JOUR
T1 - Exosome-associated Shiga toxin 2 is released from cells and causes severe toxicity in mice
AU - Watanabe-Takahashi, Miho
AU - Yamasaki, Shinji
AU - Murata, Masayuki
AU - Kano, Fumi
AU - Motoyama, Jun
AU - Yamate, Jyoji
AU - Omi, Jumpei
AU - Sato, Waka
AU - Ukai, Hirofumi
AU - Shimasaki, Kentaro
AU - Ikegawa, Masaya
AU - Tamura-Nakano, Miwa
AU - Yanoshita, Ryohei
AU - Nishino, Yuri
AU - Miyazawa, Atsuo
AU - Natori, Yasuhiro
AU - Toyama-Sorimachi, Noriko
AU - Nishikawa, Kiyotaka
N1 - Funding Information:
We thank Dr. Mari Shimura (Department of Intractable Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan) for fruitful discussion. We also thank Mika Fukumoto and Masako Yoshida (Doshisha University, Kyoto, Japan.) for technical assistance. This work was supported by a grant from Ministry of Education, Culture, Sports, Science, and Technology (MEXT)-Supported Program for the Strategic Research Foundation at Private Universities; grants from Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers 24390035, 15K08480 and 18K07128; a grant from the Research Program on Emerging and Reemerging Infectious Diseases from the Japan Agency for Medical Research and Development (AMED); a grant from the Research Program on Development of New Drugs from AMED; and a grant from the National Center for Global Health and Medicine (for N. T.-S., 21S106).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Shiga toxin (Stx), a major virulence factor of enterohemorrhagic Escherichia coli (EHEC), is classified into two subgroups, Stx1 and Stx2. Clinical data clearly indicate that Stx2 is associated with more severe toxicity than Stx1, but the molecular mechanism underlying this difference is not fully understood. Here, we found that after being incorporated into target cells, Stx2, can be transported by recycling endosomes, as well as via the regular retrograde transport pathway. However, transport via recycling endosome did not occur with Stx1. We also found that Stx2 is actively released from cells in a receptor-recognizing B-subunit dependent manner. Part of the released Stx2 is associated with microvesicles, including exosome markers (referred to as exo-Stx2), whose origin is in the multivesicular bodies that formed from late/recycling endosomes. Finally, intravenous administration of exo-Stx2 to mice causes more lethality and tissue damage, especially severe renal dysfunction and tubular epithelial cell damage, compared to a free form of Stx2. Thus, the formation of exo-Stx2 might contribute to the severity of Stx2 in vivo, suggesting new therapeutic strategies against EHEC infections.
AB - Shiga toxin (Stx), a major virulence factor of enterohemorrhagic Escherichia coli (EHEC), is classified into two subgroups, Stx1 and Stx2. Clinical data clearly indicate that Stx2 is associated with more severe toxicity than Stx1, but the molecular mechanism underlying this difference is not fully understood. Here, we found that after being incorporated into target cells, Stx2, can be transported by recycling endosomes, as well as via the regular retrograde transport pathway. However, transport via recycling endosome did not occur with Stx1. We also found that Stx2 is actively released from cells in a receptor-recognizing B-subunit dependent manner. Part of the released Stx2 is associated with microvesicles, including exosome markers (referred to as exo-Stx2), whose origin is in the multivesicular bodies that formed from late/recycling endosomes. Finally, intravenous administration of exo-Stx2 to mice causes more lethality and tissue damage, especially severe renal dysfunction and tubular epithelial cell damage, compared to a free form of Stx2. Thus, the formation of exo-Stx2 might contribute to the severity of Stx2 in vivo, suggesting new therapeutic strategies against EHEC infections.
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U2 - 10.1038/s41598-018-29128-9
DO - 10.1038/s41598-018-29128-9
M3 - Article
C2 - 30018364
AN - SCOPUS:85050255577
VL - 8
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 10776
ER -