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Title: Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis

The exocyst complex regulates the last steps of exocytosis, which is essential to organisms across kingdoms. In humans, its dysfunction is correlated with several significant diseases, such as diabetes and cancer progression. Investigation of the dynamic regulation of the evolutionarily conserved exocyst-related processes using mutants in genetically tractable organisms such as Arabidopsis thaliana is limited by the lethality or the severity of phenotypes. We discovered that the small molecule Endosidin2 (ES2) binds to the EXO70 (exocyst component of 70 kDa) subunit of the exocyst complex, resulting in inhibition of exocytosis and endosomal recycling in both plant and human cells and enhancement of plant vacuolar trafficking. An EXO70 protein with a C-terminal truncation results in dominant ES2 resistance, uncovering possible distinct regulatory roles for the N terminus of the protein. Ultimately, this study not only provides a valuable tool in studying exocytosis regulation but also offers a potentially new target for drugs aimed at addressing human disease.
Authors:
 [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [4] ;  [6] ;  [1] ;  [1] ;  [4] ;  [4] ;  [1] ;  [1] ;  [7] ;  [6] ;  [2] ;  [3] ;  [4] more »;  [4] ;  [1] ;  [8] ;  [7] ;  [1] ;  [1] « less
  1. Univ. of California, Riverside, CA (United States). Center for Plant Cell Biology. Inst. for Integrative Genome Biology. Dept. of Botany and Plant Sciences
  2. Univ. of California, Riverside, CA (United States). Dept. of Biochemistry
  3. Univ. of Pennsylvania, Philadelphia, PA (United States). Dept. of Biology
  4. Univ. of California, Riverside, CA (United States). Dept. of Chemistry
  5. Academy of Sciences of the Czech Republic (ASCR), Prague (Czech Republic). Inst. of Experimental Botany
  6. Univ. of California, Riverside, CA (United States). Dept. of Bioengineering
  7. Wake Forest Univ., Winston-Salem, NC (United States). Dept. of Biology. Center for Molecular Communication and Signaling
  8. Academy of Sciences of the Czech Republic (ASCR), Prague (Czech Republic). Inst. of Experimental Botany; Charles Univ., Prague (Czech Republic). Dept. of Experimental Plant Biology
Publication Date:
Grant/Contract Number:
FG02-02ER15295; NNX09AK82G; 15-14886S; NPUI LO1417
Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 113; Journal Issue: 1; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Research Org:
Univ. of California, Riverside, CA (United States); Wake Forest Univ., Winston-Salem, NC (United States); Academy of Sciences of the Czech Republic (ASCR), Prague (Czech Republic)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Aeronautic and Space Administration (NASA); Czech Science Foundation (Czech Republic)
Contributing Orgs:
Univ. of Pennsylvania, Philadelphia, PA (United States); Charles Univ., Prague (Czech Republic)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; EXO70; endosidin2; exocyst; exocytosis
OSTI Identifier:
1348366

Zhang, Chunhua, Brown, Michelle Q., van de Ven, Wilhelmina, Zhang, Zhi-Min, Wu, Bin, Young, Michael C., Synek, Lukáš, Borchardt, Dan, Harrison, Reed, Pan, Songqin, Luo, Nan, Huang, Yu-ming M., Ghang, Yoo-Jin, Ung, Nolan, Li, Ruixi, Isley, Jonathan, Morikis, Dimitrios, Song, Jikui, Guo, Wei, Hooley, Richard J., Chang, Chia-en A., Yang, Zhenbiao, Zarsky, Viktor, Muday, Gloria K., Hicks, Glenn R., and Raikhel, Natasha V.. Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis. United States: N. p., Web. doi:10.1073/pnas.1521248112.
Zhang, Chunhua, Brown, Michelle Q., van de Ven, Wilhelmina, Zhang, Zhi-Min, Wu, Bin, Young, Michael C., Synek, Lukáš, Borchardt, Dan, Harrison, Reed, Pan, Songqin, Luo, Nan, Huang, Yu-ming M., Ghang, Yoo-Jin, Ung, Nolan, Li, Ruixi, Isley, Jonathan, Morikis, Dimitrios, Song, Jikui, Guo, Wei, Hooley, Richard J., Chang, Chia-en A., Yang, Zhenbiao, Zarsky, Viktor, Muday, Gloria K., Hicks, Glenn R., & Raikhel, Natasha V.. Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis. United States. doi:10.1073/pnas.1521248112.
Zhang, Chunhua, Brown, Michelle Q., van de Ven, Wilhelmina, Zhang, Zhi-Min, Wu, Bin, Young, Michael C., Synek, Lukáš, Borchardt, Dan, Harrison, Reed, Pan, Songqin, Luo, Nan, Huang, Yu-ming M., Ghang, Yoo-Jin, Ung, Nolan, Li, Ruixi, Isley, Jonathan, Morikis, Dimitrios, Song, Jikui, Guo, Wei, Hooley, Richard J., Chang, Chia-en A., Yang, Zhenbiao, Zarsky, Viktor, Muday, Gloria K., Hicks, Glenn R., and Raikhel, Natasha V.. 2015. "Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis". United States. doi:10.1073/pnas.1521248112. https://www.osti.gov/servlets/purl/1348366.
@article{osti_1348366,
title = {Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis},
author = {Zhang, Chunhua and Brown, Michelle Q. and van de Ven, Wilhelmina and Zhang, Zhi-Min and Wu, Bin and Young, Michael C. and Synek, Lukáš and Borchardt, Dan and Harrison, Reed and Pan, Songqin and Luo, Nan and Huang, Yu-ming M. and Ghang, Yoo-Jin and Ung, Nolan and Li, Ruixi and Isley, Jonathan and Morikis, Dimitrios and Song, Jikui and Guo, Wei and Hooley, Richard J. and Chang, Chia-en A. and Yang, Zhenbiao and Zarsky, Viktor and Muday, Gloria K. and Hicks, Glenn R. and Raikhel, Natasha V.},
abstractNote = {The exocyst complex regulates the last steps of exocytosis, which is essential to organisms across kingdoms. In humans, its dysfunction is correlated with several significant diseases, such as diabetes and cancer progression. Investigation of the dynamic regulation of the evolutionarily conserved exocyst-related processes using mutants in genetically tractable organisms such as Arabidopsis thaliana is limited by the lethality or the severity of phenotypes. We discovered that the small molecule Endosidin2 (ES2) binds to the EXO70 (exocyst component of 70 kDa) subunit of the exocyst complex, resulting in inhibition of exocytosis and endosomal recycling in both plant and human cells and enhancement of plant vacuolar trafficking. An EXO70 protein with a C-terminal truncation results in dominant ES2 resistance, uncovering possible distinct regulatory roles for the N terminus of the protein. Ultimately, this study not only provides a valuable tool in studying exocytosis regulation but also offers a potentially new target for drugs aimed at addressing human disease.},
doi = {10.1073/pnas.1521248112},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 1,
volume = 113,
place = {United States},
year = {2015},
month = {11}
}