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FK506, an Immunosuppressive Drug, Induces Autophagy by Binding to the V-ATPase Catalytic Subunit A in Neuronal Cells

Kim, Dongyoung; Hwang, Hui Yun LU ; Kim, Young Jin; Lee, Ju Yeon; Yoo, Jong Shin; Marko-Varga, György LU and Kwon, Ho Jeong (2017) In Journal of Proteome Research 16(1). p.55-64
Abstract

The drug FK506 (tacrolimus, fujimycin) exerts its immunosuppressive effects by regulating the nuclear factor of the activated T-cell (NFAT) family of transcription factors. However, FK506 also exhibits neuroprotective effects, but its direct target proteins that mediate these effects have not been determined. To identify the target proteins responsible for FK506's neuroprotective effects, the drug affinity responsive target stability (DARTS) method was performed using label-free FK506, and LC-MS/MS analysis of the FK506-treated proteome was also performed. Using DARTS and LC-MS/MS analyses in combination with reference studies, V-ATPase catalytic subunit A (ATP6V1A) was identified as a new target protein of FK506. The biological... (More)

The drug FK506 (tacrolimus, fujimycin) exerts its immunosuppressive effects by regulating the nuclear factor of the activated T-cell (NFAT) family of transcription factors. However, FK506 also exhibits neuroprotective effects, but its direct target proteins that mediate these effects have not been determined. To identify the target proteins responsible for FK506's neuroprotective effects, the drug affinity responsive target stability (DARTS) method was performed using label-free FK506, and LC-MS/MS analysis of the FK506-treated proteome was also performed. Using DARTS and LC-MS/MS analyses in combination with reference studies, V-ATPase catalytic subunit A (ATP6V1A) was identified as a new target protein of FK506. The biological relevance of ATP6V1A in mediating the neuroprotective effects of FK506 was validated by analyzing FK506 activity with respect to autophagy via acridine orange staining and transcription factor EB (TFEB) translocation assay. These analyses demonstrated that the binding of FK506 with ATP6V1A induces autophagy by activating the translocation of TFEB from the cytosol into the nucleus. Because autophagy has been identified as a mechanism for treating neurodegenerative diseases and because we have demonstrated that FK506 induces autophagy, this study demonstrates that FK506 is a possible new therapy for treating neurodegenerative diseases.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
autophagy, DARTS, FK506, LC-MS/MS, neuroprotective activity, TFEB translocation, V-ATPase
in
Journal of Proteome Research
volume
16
issue
1
pages
10 pages
publisher
The American Chemical Society
external identifiers
  • scopus:85017592664
  • wos:000391782100007
ISSN
1535-3893
DOI
10.1021/acs.jproteome.6b00638
language
English
LU publication?
yes
id
38d5d164-30d1-4c19-91f3-1620e1df3e69
date added to LUP
2017-05-08 15:31:02
date last changed
2017-09-18 11:35:27
@article{38d5d164-30d1-4c19-91f3-1620e1df3e69,
  abstract     = {<p>The drug FK506 (tacrolimus, fujimycin) exerts its immunosuppressive effects by regulating the nuclear factor of the activated T-cell (NFAT) family of transcription factors. However, FK506 also exhibits neuroprotective effects, but its direct target proteins that mediate these effects have not been determined. To identify the target proteins responsible for FK506's neuroprotective effects, the drug affinity responsive target stability (DARTS) method was performed using label-free FK506, and LC-MS/MS analysis of the FK506-treated proteome was also performed. Using DARTS and LC-MS/MS analyses in combination with reference studies, V-ATPase catalytic subunit A (ATP6V1A) was identified as a new target protein of FK506. The biological relevance of ATP6V1A in mediating the neuroprotective effects of FK506 was validated by analyzing FK506 activity with respect to autophagy via acridine orange staining and transcription factor EB (TFEB) translocation assay. These analyses demonstrated that the binding of FK506 with ATP6V1A induces autophagy by activating the translocation of TFEB from the cytosol into the nucleus. Because autophagy has been identified as a mechanism for treating neurodegenerative diseases and because we have demonstrated that FK506 induces autophagy, this study demonstrates that FK506 is a possible new therapy for treating neurodegenerative diseases.</p>},
  author       = {Kim, Dongyoung and Hwang, Hui Yun and Kim, Young Jin and Lee, Ju Yeon and Yoo, Jong Shin and Marko-Varga, György and Kwon, Ho Jeong},
  issn         = {1535-3893},
  keyword      = {autophagy,DARTS,FK506,LC-MS/MS,neuroprotective activity,TFEB translocation,V-ATPase},
  language     = {eng},
  month        = {01},
  number       = {1},
  pages        = {55--64},
  publisher    = {The American Chemical Society},
  series       = {Journal of Proteome Research},
  title        = {FK506, an Immunosuppressive Drug, Induces Autophagy by Binding to the V-ATPase Catalytic Subunit A in Neuronal Cells},
  url          = {http://dx.doi.org/10.1021/acs.jproteome.6b00638},
  volume       = {16},
  year         = {2017},
}