FKBP8 recruits LC3A to mediate Parkin‐independent mitophagy

• Published in: EMBO reports 2017-06, Vol.18 (6), p.947-961
• Main Authors: Bhujabal, Zambarlal, Birgisdottir, Åsa B, Sjøttem, Eva, Brenne, Hanne B, Øvervatn, Aud, Habisov, Sabrina, Kirkin, Vladimir, Lamark, Trond, Johansen, Terje
• Format: Article
• Language: English
• Subjects: Apoptosis; Autophagy; Biodegradation; BNIP3 protein; Cell survival; Damage; Degradation; EMBO07; EMBO20; FKBP38; FKBP8; GABARAP protein; HeLa Cells; Homeostasis; Humans; In vitro methods and tests; LC3A; Membrane Proteins - genetics; Membrane Proteins - metabolism; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Mitochondria; Mitochondrial Membranes - metabolism; Mitochondrial Proteins - metabolism; Mitophagy; Parkin protein; Phagocytosis; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Receptors; Recruitment; Saccharomyces cerevisiae - metabolism; Tacrolimus; Tacrolimus Binding Proteins - genetics; Tacrolimus Binding Proteins - metabolism; Tacrolimus-binding protein; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Two-Hybrid System Techniques; Ubiquitin-Protein Ligases - metabolism; Yeast; Yeasts
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201643147

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. Synopsis FKBP8 (also called FKBP38) is a novel mitophagy receptor that selectively recruits LC3A to damaged mitochondria to mediate Parkin‐independent degradation of mitochondria by autophagy. The anti‐apoptotic FKBP8 itself escapes degradation to ensure cell survival. FKBP8 binds to LC3A via an N‐terminal LIR motif. FKBP8 recruits lipidated LC3A to damaged mitochondria in a Parkin‐independent manner. Co‐expression of FKBP8 and LC3A induces efficient Parkin‐independent mitophagy. FKBP8 escapes from the mitochondria destined for autophagic degradation after having recruited LC3A. Graphical Abstract FKBP8 (also called FKBP38) is a novel mitophagy receptor that selectively recruits LC3A to damaged mitochondria to mediate Parkin‐independent degradation of mitochondria by autophagy. The anti‐apoptotic FKBP8 itself escapes degradation to ensure cell survival.