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

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Dongyoung Kim
  • Hui Yun Hwang
  • Young Jin Kim
  • Ju Yeon Lee
  • Jong Shin Yoo
  • György Marko-Varga
  • Ho Jeong Kwon
Organisations
External organisations
  • Yonsei University
  • Korea Basic Science Institute
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area
  • Cell and Molecular Biology

Keywords

  • autophagy, DARTS, FK506, LC-MS/MS, neuroprotective activity, TFEB translocation, V-ATPase
Original languageEnglish
Pages (from-to)55-64
Number of pages10
JournalJournal of Proteome Research
Volume16
Issue number1
Publication statusPublished - 2017 Jan 6
Publication categoryResearch
Peer-reviewedYes