Biological Roles of Alternative Autophagy

Abstract

Atg5 and Atg7 have long been considered as essential molecules for autophagy. However, we found that cells lacking these molecules still form autophagic vacuoles and perform autophagic protein degradation when subjected to certain stressors. During this unconventional autophagy pathway, autophagosomes appeared to be generated in a Rab9-dependent manner by the fusion of vesicles derived from the trans-Golgi and late endosomes. Therefore, mammalian autophagy can occur via at least two different pathways; the Atg5/Atg7-dependent conventional pathway and an Atg5/Atg7-independent alternative pathway.

Keywords: Atg5; Golgi membrane; alternative autophagy; erythrocyte maturation; proteolysis.

Fig. 1. Hypothetical model of autophagy

There are at least two modes of macroautophagy, i.e. conventional and alternative autophagy. Conventional autophagy requires Atg5 and Atg7, is associated with LC3 modification, and is thought to originate from the ER membrane. In contrast, alternative autophagy occurs independently of Atg5 and Atg7, as well as LC3 modification. The generation of autophagic vacuoles in alternative autophagy is mediated by the fusion of isolation membranes with vesicles derived from the trans-Golgi as well as late endosomes, in a Rab9-dependent manner.

Fig. 2. Involvement of alternative autophagy in mitochondrial clearance during erythrocyte maturation

(A) The final stage of red blood cell maturation. During erythrocyte maturation, erythroblasts lose their nuclei to become reticulocytes, and reticulocytes transform into erythrocytes by the elimination of their mitochondria. Autophagy is involved in the latter process. (B) Mechanism of mitochondrial elimination during erythrocyte maturation. Mitochondrial elimination mainly occurs via Ulk1-dependent alternative autophagy and only partially via Atg5-dependent conventional autophagy.