Autophagy Process

By Dr Ananya Mandal, MD

The process of autophagy has been conserved over time among all living organisms. The process is similar in single cellular organisms like yeast to multi-cellular organisms like humans. The process is a dynamic one but can be divided into some basic steps:-

Induction

Autophagy is induced when the cell is put under stress or there is depletion of growth factors and/or nutrients in the media where the cell resides.

There are usually intracellular stimuli and signals that induce autophagy. One of the regulatory targets in the cell that is stimulated when autophagy is induced is the protein kinase target of rapamycin (Tor). Tor either directly or indirectly controls a protein complex that is sometimes called the switching complex.

Cargo selection and packaging

As the signals for autophagy are in place and there is induction of the process, the next step is to select the material that is to be removed or broken down. This is termed cargo.

The cargo is selectively separated and is packaged inside vacuoles. This is a receptor-mediated route transport. A vesicle with the cargo is formed.

Completion of the sequestering vesicle results from complex interactions between proteins. Once fused with the vacuole the inner vesicle is released into the lumen and the whole thing is called the Cvt body.

Vesicle nucleation

The next step of the process is formation of the sequestered vesicle. This is the main site that assembles and organizes the autophagy machinery.

Once sequestered the intracellular membranes form a cup-shaped structure around the cargo. The intermediate structure is termed a phagophore, or isolation membrane.

Vesicle expansion and completion

The membrane expands to completely enclose the cargo. Several important proteins play a role in this step. This step gives rise to the autophagosomes.

Retrieval

In this step the proteins that were involved in the previous steps must dissociate from the autophagosome. This is particularly problematic for integral membrane proteins like Atg9 that cannot separate from the vesicle. Most of the other proteins may be reused.

Targeting, docking and fusion of the vesicle with the lysosome/vacuole

The next step is to prevent the fusion of the incomplete Cvt vesicle or autophagosome with the lysosome or vacuole. This is done by special coat proteins present on their surfaces.

Once the vesicle is complete, it goes on to fuse with the degradative organelle. This forms an endosome.

Breakdown of the vesicle and its contents

The final step is breakdown of the vesicle and release of its cargo. The outer membrane of the sequestering vesicle breaks to become continuous with the membrane of the lysosome/vacuole.

This membrane is then removed through a microautophagic process. Opening of the vesicle by breaking down of the membrane releases the contents of the lumen.

Reviewed by April Cashin-Garbutt, BA Hons (Cantab)

Sources

  1. http://www.cellsignal.com/reference/pathway/pdfs/Autophagy.pdf
  2. http://www.wiley-vch.de/books/sample/3527314504_c01.pdf
  3. http://myweb.sabanciuniv.edu/dgozuacik/files/2009/01/curr-top-in-devel-review2.pdf
  4. http://morelife.org/references/full_papers/16973211.pdf
  5. http://users.unimi.it/minucci/BARB%202011-2012/Lecture%20of%20Autophagy%2014-11-11%20Elgendy/Lecture%20Autophagy-%20pdf.pdf
  6. http://xa.yimg.com/kq/groups/15186538/1192184234/name/Anita's+1st+Article.pdf

Further Reading

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