Liquidity Is a Critical Determinant for Selective Autophagy of Protein Condensates

• Published in: Molecular cell 2020-03, Vol.77 (6), p.1163-1175.e9
• Main Authors: Yamasaki, Akinori, Alam, Jahangir Md, Noshiro, Daisuke, Hirata, Eri, Fujioka, Yuko, Suzuki, Kuninori, Ohsumi, Yoshinori, Noda, Nobuo N.
• Format: Article
• Language: English
• Subjects: autophagic receptor; autophagy; biomolecular condensates; Cvt pathway; floatability; liquidity; phase separation; selective autophagy
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2019.12.026

Clearance of biomolecular condensates by selective autophagy is thought to play a crucial role in cellular homeostasis. However, the mechanism underlying selective autophagy of condensates and whether liquidity determines a condensate’s susceptibility to degradation by autophagy remain unknown. Here, we show that the selective autophagic cargo aminopeptidase I (Ape1) undergoes phase separation to form semi-liquid droplets. The Ape1-specific receptor protein Atg19 localizes to the surface of Ape1 droplets both in vitro and in vivo, with the “floatability” of Atg19 preventing its penetration into droplets. In vitro reconstitution experiments reveal that Atg19 and lipidated Atg8 are necessary and sufficient for selective sequestration of Ape1 droplets by membranes. This sequestration is impaired by mutational solidification of Ape1 droplets or diminished ability of Atg19 to float. Taken together, we propose that cargo liquidity and the presence of sufficient amounts of autophagic receptor on cargo are crucial for selective autophagy of biomolecular condensates. [Display omitted] •Ape1 undergoes phase separation to form semi-liquid droplets•Floatability of Atg19 mediates condensation of Atg19 on the surface of Ape1 droplets•Atg19 and Atg8-PE are sufficient for selective membrane sequestration of Ape1 droplets•Liquidity of Ape1 droplets is important for selective autophagy Selective autophagy contributes to cellular homeostasis through clearance of biomolecular condensates. Yamasaki et al. find that the liquidity of protein condensates is a critical determinant for its selective membrane sequestration and that selective autophagy of liquid droplets is mediated by a receptor with floatability.