Autophagy research in the past three decades has provided a detailed parts list of the initiation machinery. However, the regulation of its assembly and disassembly remains enigmatic. We summarize the role of HORMA domain proteins ATG13 and ATG101 in autophagosome biogenesis and explore how their hypothetical catalysed metamorphosis could be a responsive switch to conditionally activate autophagy initiation.

Autophagy is a process of regulated degradation. It eliminates damaged and unnecessary cellular components by engulfing them with a de novo-generated organelle: the double-membrane autophagosome. The past three decades have provided us with a detailed parts list of the autophagy initiation machinery, have developed important insights into how these processes function and have identified regulatory proteins. It is now clear that autophagosome biogenesis requires the timely assembly of a complex machinery. However, it is unclear how a putative stable machine is assembled and disassembled and how the different parts cooperate to perform its overall function. Although they have long been somewhat enigmatic in their precise role, HORMA domain proteins (first identified in Hop1p, Rev7p and MAD2 proteins) autophagy-related protein 13 (ATG13) and ATG101 of the ULK-kinase complex have emerged as important coordinators of the autophagy-initiating subcomplexes. Here, we will particularly focus on ATG13 and ATG101 and the role of their unusual metamorphosis in initiating autophagosome biogenesis. We will also explore how this metamorphosis could potentially be purposefully rate-limiting and speculate on how it could regulate the spontaneous self-assembly of the autophagy-initiating machinery.