Abstract

Selective autophagy, the selective degradation of macromolecules or organelles by autophagy, is a crucial quality control process vital for cellular homeostasis and prevention of disease. Cargoes to be degraded are recognized by selective autophagy receptors, like the Sequestosome 1/p62-Like Receptors (SLRs). p62/SQSTM1 and other SLRs couple cargo to the forming autophagosomes, called phagophores, via interactions with the ATG8 family of proteins through a short motif in the autophagy receptors, the LIR motif. ATG8 family proteins are also involved in scaffolding the autophagosome nucleation machinery. We have found that both the ULK1 /2- and class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1) complexes as well as ATG4B rely on GABARAP subfamily ATG8 proteins for membrane scaffolding interactions. The targeted clearance of surplus, damaged or dysfunctional mitochondria by autophagy (mitophagy) is one of the most important selective autophagy processes. SLRs are involved in mitophagy in addition to the membrane-bound mitophagy receptors. In a collaborative effort between our group and the group of Anne Simonsen we have found that the mitochondrial matrix proteins NIPSNAP1 (4-Nitrophenylphosphatase domain and non-neuronal SNAP25 -like protein homolog 1) and NIPSNAP2 accumulate on the mitochondrial surface upon mitochondrial depolarization. There they recruit SLRs and ATG8 proteins, thereby functioning as “eat-me” signals for mitophagy. In another study, we have uncovered a novel mitophagy receptor that collaborates with the archetypical SLR , p62/SQSTM1 in the turnover of a subset of mitochondrial membrane proteins by piecemeal basal mitophagy.