Researchers recreate the machine which cleans up the waste inside a cell

Suppose, If this autophagy process, for some reason, is unstable, and there’s an accumulation of junk in your cells. In that case, it may lead to neurodegenerative diseases and in some cases, even cancer.

But what starts and then stops the assembly of the autophagy machine?

To understand the fundamental gaps in their knowledge regarding the beginning of the autophagy process, a German team of researchers took several years to produce all the proteins involved in the process.

"How do the protein components work together? How is the process of autophagy started and stopped? When and where is the autophagosome assembled? That is what we want to find out," said Alex Faesen, research group leader at the Max Planck Institute for Multidisciplinary Sciences in Göttingen, in a statement.

The team observed the proteins directly as the autophagosomes assembled. The standard approach is to use genetically reprogrammed bacteria. "But protein production with bacteria did not work for any of our proteins," said Faesen. 

The scientists had a breakthrough moment when they switched to insect cells as molecular helpers instead.

The next step involved bringing the individual protein complexes together. "The complexes self-assembled into a protein supercomplex, the autophagy initiation complex. Autophagy involves a sophisticated cellular nanomachine—and it works quite differently than previously thought," explained Faesan.

Autophagosomes are formed within minutes when a body comes under stress from activities like endurance sports or during times of starvation. “From this point on, there is no turning back: The waste disposal is assembled and collects the cellular waste,” explains Anh Nguyen, one of the two first authors of the study now published in Molecular Cell. 

Although the research team recreated this nanomachine, there are still some unanswered questions related to the molecular ‘on’ and ‘off’ switch, as is present in other molecular machines.

The researchers hope that their insights could contribute to the treatment of cancer and neurodegenerative diseases and delay the process of aging.

The study was published in the journal Molecular Cell.

Study abstract:

Autophagy is a conserved intracellular degradation pathway that generates de novo double-membrane autophagosomes to target a wide range of material for lysosomal degradation. In multicellular organisms, autophagy initiation requires the timely assembly of a contact site between the ER and the nascent autophagosome. Here, we report the in vitro reconstitution of a full-length seven-subunit human autophagy initiation supercomplex built on a core complex of ATG13-101 and ATG9. Assembly of this core complex requires the rare ability of ATG13 and ATG101 to switch between distinct folds. The slow spontaneous metamorphic conversion is rate limiting for the self-assembly of the supercomplex. The interaction of the core complex with ATG2-WIPI4 enhances tethering of membrane vesicles and accelerates lipid transfer of ATG2 by both ATG9 and ATG13-101. Our work uncovers the molecular basis of the contact site and its assembly mechanisms imposed by the metamorphosis of ATG13-101 to regulate autophagosome biogenesis in space and time.