FKBP8 recruits LC3A to mediate Parkin-independent mitophagy

EMBO Rep. 2017 Jun;18(6):947-961. doi: 10.15252/embr.201643147. Epub 2017 Apr 5.

Abstract

Mitophagy, the selective removal of damaged or excess mitochondria by autophagy, is an important process in cellular homeostasis. The outer mitochondrial membrane (OMM) proteins NIX, BNIP3, FUNDC1, and Bcl2-L13 recruit ATG8 proteins (LC3/GABARAP) to mitochondria during mitophagy. FKBP8 (also known as FKBP38), a unique member of the FK506-binding protein (FKBP) family, is similarly anchored in the OMM and acts as a multifunctional adaptor with anti-apoptotic activity. In a yeast two-hybrid screen, we identified FKBP8 as an ATG8-interacting protein. Here, we map an N-terminal LC3-interacting region (LIR) motif in FKBP8 that binds strongly to LC3A both in vitro and in vivo FKBP8 efficiently recruits lipidated LC3A to damaged mitochondria in a LIR-dependent manner. The mitophagy receptors BNIP3 and NIX in contrast are unable to mediate an efficient recruitment of LC3A even after mitochondrial damage. Co-expression of FKBP8 with LC3A profoundly induces Parkin-independent mitophagy. Strikingly, even when acting as a mitophagy receptor, FKBP8 avoids degradation by escaping from mitochondria. In summary, this study identifies novel roles for FKBP8 and LC3A, which act together to induce mitophagy.

Keywords: FKBP38; FKBP8; LC3A; autophagy; mitophagy.

MeSH terms

  • HeLa Cells
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / metabolism
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins / metabolism
  • Mitophagy*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Saccharomyces cerevisiae / metabolism
  • Tacrolimus Binding Proteins / genetics*
  • Tacrolimus Binding Proteins / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Two-Hybrid System Techniques
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • BCL2 protein, human
  • BNIP3 protein, human
  • BNIP3L protein, human
  • FKBP8 protein, human
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Proteins
  • light chain 3, human
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Tacrolimus Binding Proteins