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FKBP8 recruits LC3A to mediate Parkin-independent mitophagy
Zambarlal Bhujabal1, Åsa B Birgisdottir1, Eva Sjøttem1
1Molecular Cancer Research Group, Department of Medical Biology, University of Tromsø -The Arctic University of Norway, Tromsø, Norway.
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.
Insights
FKBP8 acts as a novel mitophagy receptor, recruiting LC3A to damaged mitochondria to promote cellular homeostasis. This process is Parkin-independent and FKBP8 avoids degradation.
Area of Science:
- Cell Biology
- Molecular Biology
- Autophagy Research
Background:
- Mitophagy is crucial for cellular homeostasis, involving outer mitochondrial membrane (OMM) proteins that recruit ATG8 proteins (e.g., LC3/GABARAP).
- Known mitophagy receptors include NIX, BNIP3, FUNDC1, and Bcl2-L13, which facilitate the selective removal of damaged mitochondria.
- FKBP8, an OMM-anchored FKBP family member, possesses anti-apoptotic functions and has been identified as an ATG8-interacting protein.
Purpose of the Study:
- To investigate the role of FKBP8 in mitophagy.
- To characterize the interaction between FKBP8 and ATG8 proteins, specifically LC3A.
- To determine if FKBP8 functions as a mitophagy receptor and its mechanism of action.
Main Methods:
- Yeast two-hybrid screening to identify ATG8-interacting proteins.
- In vitro and in vivo binding assays to map the LC3-interacting region (LIR) of FKBP8.
- Mitochondrial damage induction and assessment of LC3A recruitment.
- Co-expression studies with FKBP8 and LC3A to evaluate mitophagy induction.
- Analysis of FKBP8 stability during mitophagy.
Main Results:
- FKBP8 possesses an N-terminal LIR motif that strongly binds LC3A.
- FKBP8 efficiently recruits lipidated LC3A to damaged mitochondria in a LIR-dependent manner.
- Compared to BNIP3 and NIX, FKBP8 mediates more efficient LC3A recruitment to damaged mitochondria.
- Co-expression of FKBP8 and LC3A induces significant Parkin-independent mitophagy.
- FKBP8 escapes degradation during mitophagy, unlike other mitophagy receptors.
Conclusions:
- FKBP8 is identified as a novel mitophagy receptor that interacts with LC3A.
- FKBP8 and LC3A cooperate to induce Parkin-independent mitophagy.
- FKBP8's ability to avoid degradation distinguishes its role as a mitophagy receptor.