Disputation: Morten Luhr – Cell biology
Morten Luhr at Centre for Molecular Medicine Norway will be defending the thesis “The unfolded protein response and the ATG8 protein family in autophagy” for the degree of Philosophiae doctor.
Trial lecture - time and place
See trial lecture.
- First opponent: Professor Mario Tschan, Universität Bern
- Second opponent: Associate Professor Eva Sjøtten, UiT - Norges arktiske universitet
- Third member of the adjudication committee: Associate Professor Knut Tomas Dalen, University of Oslo
Chair of defence
Professor Thor Willy Ruud Hansen, University of Oslo
Project Manager Nikolai Engedal, Centre for Molecular Medicine Norway
Autophagy is a catabolic process whereby cytoplasmic material is sequestered into double- or multi-membrane vesicles, which subsequently fuse with lysosomes. The sequestered material is then degraded and released back into the cytosol where it is recycled. Because of its role in maintaining homeostasis and in determining cell fate in response to stress, understanding how autophagy is regulated is paramount.
When misfolded proteins accumulate in the endoplasmic reticulum (“ER stress”), the unfolded protein response (UPR) is triggered. The UPR initially attempts to rescue cells from stress, but can promote cell death if this is not achieved. Reports have proposed that autophagy may be upregulated in response to ER stress, and that it influences whether cells survive or succumb to the stress. However, because insufficient methods have been employed to arrive at this conclusion, the relationship between ER stress/UPR and autophagy is not well understood.
Here, we substantially improved classical biochemical methods for assessing autophagic cargo sequestration and degradation in mammalian cells. This enabled us to demonstrate that the LC3 proteins are dispensable for starvation-induced autophagy, whereas the other ATG8 protein subfamily, the GABARAPs, is essential. Next, we investigated our main aim: how ER stress and the UPR affect autophagic activity. We found that ER stress induces bulk autophagy in a manner that requires the UPR components PERK and ATF4. Moreover, the LC3s were redundant also for ER stress-induced autophagy, whereas the GABARAPs were required. Importantly, we found that PERK and ATF4 were functionally uncoupled and regulated autophagy at different steps. Whereas PERK was required after autophagosome formation, ATF4 acted at a step prior to phagophore closure. In summary, this work advanced autophagy methodology, uncovered a central role for the GABARAPs in bulk autophagy, and revealed new functions of PERK and ATF4 in ER stress-induced autophagy.
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