Research Group REGGIORI

Faculty of Medicine, UMC Utrecht, Dept. of Cell Biology
Contact: Dr. Fulvio Reggiori
E-mail: F.Reggiori@umcutrecht.nl
Website: http://www.cellbiology-utrecht.nl/groups/reggiori/index.html

General research focus: Autophagy and the process of autophagosome formation

Autophagy is a degradative process conserved among all eukaryotic cells and is required for the rapid degradation of large portions of the cytoplasm and of unnecessary or damaged organelles in the lysosome lumen. It has long been known that this catabolic pathway is essential to generate an internal pool of nutrients that permit cells to survive during prolonged periods of starvation. Recent studies however, have revealed that autophagy actively participates in other cellular processes such as development, cellular differentiation and rearrangement, aging, elimination of aberrant structures and type II programmed cell death. Autophagy also contributes to the cell's defense against pathogens (both viruses and bacteria) and tumors. Consequently, defects in this protective barrier correlate with a growing list of diseases, including cancer, neurodegenerative disorders such as Huntington's, Parkinson's and Alzheimer's diseases, and cardiomyopathies.
The main morphological feature of autophagy is the sequestration of the cargo targeted for destruction by a large cytosolic double-membrane vesicle called an autophagosome that delivers it into the lysosome/vacuole interior for destruction. Despite the identification of many specific components, the Atg proteins, the molecular mechanism that directs formation of the sequestering vesicles remains largely unknown.

Research Lines

A major challenge in unveiling the process of autophagosome formation arises from the fact that the origin and the transport mode of the lipids employed to compose these structures are unknown. Atg9 is the only integral membrane protein essential for this process. Despite playing a key role in autophagy, the Atg9 molecular function is still unknown and its amino acid sequence does not provide any clue (as in the case for all other Atg proteins). This protein is probably transported to the PAS with at least part of the lipid bilayers required to create this structure. The fact that Atg9 is associated with membranes during its entire life cycle makes this a highly interesting protein to study the membrane traffic events during autophagosome biogenesis.
We have demonstrated that Atg9 cycles between the pre-autophagosomal structure, the site where autophagosomes are formed, and several cytoplasmic punctate structures, supporting the idea that it could supply the forming autophagosomes with (part of) its membranes. In particular, we have revealed that 4 further Atg proteins catalyze its recycling from the PAS. We have recently shown that part of these unknown punctate structures are Atg9 complexes on the mitochondrial surface. A lot of questions about Atg9, however, still remain unanswered. Which factors mediate Atg9 sorting from mitochondria? How is Atg9 transported? Where are the remaining Atg9 complexes that are not on the mitochondrial surface? What is the function of Atg9?

Techniques:

In our research, a combination of genetic, molecular biological, biochemical, and microscopical (fluorescence and electron microscopy) techniques is applied to both yeast Saccharomyces cerevisiae and mammalian cells.

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