Selective binding of mitophagy receptor protein Bcl-rambo to LC3/GABARAP family proteins

Abstract

Mitophagy regulates the metabolic level and cell fates by specifically degrading damaged or redundant mitochondria in these cells. During the formation of autophagosomes, autophagy receptors and adaptors, which usually contain a LC3-interacting region (LIR) domain, are recruited through their interactions with LC3/GABARAP family of proteins. Bcl-rambo is one of the mitophagy receptors that interact with LC3s/GABARAPs. In this study, we first measured the binding of Bcl-rambo to LC3s/GABARAPs in vitro and found Bcl-rambo has a selectivity to LC3C/GABARP/GABARAPL1. Further investigations with bioinformatics analyses and mutagenesis suggested that the interactions with the HP1 and HP2 sites of LC3s/GABARAPs and the residues at the X₂ site of the LIR domain of Bcl-rambo are both critical for the selectivity. Moreover, assays in vivo showed that manipulating the selective binding of Bcl-rambo resulted in the changes of mitophagy inductions in the cells. Overall, our data revealed the selective binding between Bcl-rambo and LC3s/GABARAPs and its molecular mechanisms and biological significances, which will be helpful for future studies of mitophagy mediated by Bcl-rambo.

Keywords: Bcl-rambo; LC3s/GABARAPs; Mitophagy; Selective binding.