Alternative macroautophagic pathways lead to lysosomal degradation. At least four autophagic pathways can be distinguished that all show double-membrane autophagic structures and end in lysosomal degradation of cytoplasmic cargo. Conventional macroautophagy is hallmarked by the recruitment of lipidated LC3 to autophagosomal membranes that may origin from the endoplasmatic reticulum (ER). This process is dependent on Atg5 and Beclin 1 and can be inhibited by 3-methyladenine (3-MA). In contrast, the observed Atg5/Atg7-independent autophagy pathway forms Rab9-positive double-membrane vesicles derived from the trans-Golgi network and late endosomes (LE), and while it can be inhibited by 3-MA and is dependent on Beclin 1, the process is independent of Atg5 and LC3. Almost similar, the degradation of accumulated peptidase-resistant peptides is independent of Atg5 and LC3 and is also insensitive to 3-MA treatment. Finally, the noncanonical autophagy pathway induced by different stress factors is dependent on Atg5 and LC3 and independent of Beclin 1 but cannot be impaired by 3-MA.
