The Autophagy Team
The Autophagy Team is an independent research group, focusing on intracellular processes that lead to sequestration and degradation of the cytoplasm ("autophagy")
The Autophagy Team (from left): Per O. Seglen (Guest researcher), Nikolai Engedal (Team Leader), Frank Sætre (Head engineer), Morten Luhr (PhD fellow), Paula Szalai (PhD fellow). Photo: Jorunn Valle Nilsen (Norwegian Cancer Society). Photo: Ingvild Vaale Arnesen/Kreftforeningen
About the Autophagy Team
The Autophagy Team aims to understand central regulatory mechanisms and mediators of autophagic processes in mammalian cells. Autophagy plays a key role in human physiology, and its dysregulation is implicated in many diseases. We have a particular interest in the role of autophagy in cancer.
Specifically, we study:
- Regulation of autophagy by calcium perturbation and signaling from ER stress / the unfolded protein response (UPR) in malignant and nonmalignant cells.
- Intersections between autophagy and apoptosis under ER stress conditions, and mechanisms of cell death induced by therapeutically relevant anti-cancer drugs.
- The role of autophagy-related genes (Atgs) in basal, starvation, and stress-induced autophagy in mammalian cells.
- Regulation of autophagosome completion.
- A novel form of autophagy identified in primary rat hepatocytes.
Our Team is a member of the Nordic Autophagy Network, where Engedal is a coordinator and Steering Board member, and the Trans AUTOPHAGY EU COST action. CA15138, where Engedal is a Task Manager and Norwegian representative on the Board.
- Nikolai Engedal, Team Leader
- Morten Luhr, PhD Fellow
- Paula Szalai, PhD Fellow
- Frank Ove Sætre, Head Engineer (50% position)
- Per Ottar Seglen, Guest Researcher (60% position)
Sehgal P, Szalai P, Ylanko J, Olesen C, Praetorius HA, Nissen P, Andrews DW, Christensen SB, Engedal N*, Møller JV. Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+ depletion and the unfolded protein response. J Biol Chem. 2017 Sep 29. pii: jbc.M117.796920. doi: 10.1074/jbc.M117.796920. * Co-corresponding author
Kjos I, Distefano MB, Sætre F, Repnik U, Holland P, Jones A, Engedal N, Simonsen A, Bakke O, Progida C. Rab7b modulates autophagic flux by interacting with Atg4B. EMBO Rep. 2017 Oct;18(10):1727-1739.
Vdovikova S, Luhr M, Szalai P, Nygård Skalman L, Francis MK, Lundmark R, Engedal N*,Johansson J, Wai SN. A Novel Role of Listeria monocytogenes Membrane Vesicles in Inhibition of Autophagy and Cell Death. Front Cell Infect Microbiol, 2017 May 3;7:154. * Co-corresponding author
Luhr M, Szalai P, Sætre F, Gerner L, Seglen PO, Engedal N. A simple cargo sequestration assay for quantitative measurement of non-selective autophagy in cultured cells. Methods Enzymol, 2017;587:351-364.
Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, Adachi H, Adams CM, Adams PD, Adeli K, Adhihetty PJ, Adler SG, Agam G, …. Engedal N … Seglen PO… et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy, 2016, 12(1):1-222
Engedal N, Seglen PO. Autophagy of cytoplasmic bulk cargo does not require LC3. Autophagy, 2016, 12(2):439-41
Saetre F, Hagen LK, Engedal N, Seglen PO. Novel steps in the autophagic-lysosomal pathway. FEBS J, 2015, 282(11):2202-14
Szalai P, Hagen LK, Sætre F, Luhr M, Sponheim M, Øverbye A, Mills IG, Seglen PO, Engedal N. Autophagic bulk sequestration of cytosolic cargo is independent of LC3, but requires GABARAPs. Exp Cell Res, 2015, 333(1):21-38
Seglen PO, Luhr M, Mills IG, Sætre F, Szalai P, Engedal N. Macroautophagic cargo sequestration assays. Methods, 2015, 75:25-36
Itkonen HM, Engedal N, Babaie E, Luhr M, Guldvik IJ, Minner S, Hohloch J, Tsourlakis MC, Schlomm T, Mills IG. UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation. Oncogene, 2015, 34(28):3744-50
Engedal N, Mills IG. Endosomal signaling and oncogenesis. Methods Enzymol, 2014;535:179-200
Patel KK1, Miyoshi H, Beatty WL, Head RD, Malvin NP, Cadwell K, Guan JL, Saitoh T, Akira S, Seglen PO, Dinauer MC, Virgin HW, Stappenbeck TS. Autophagy proteins control goblet cell function by potentiating reactive oxygen species production. EMBO J, 2013, 32(24):3130-44.
Engedal N, Torgersen ML, Guldvik IJ, Barfeld SJ, Bakula D, Sætre F, Hagen LK, Patterson JB, Proikas-Cezanne T, Seglen PO, Simonsen A, Mills IG. Modulation of intracellular calcium homeostasis blocks autophagosome formation. Autophagy, 2013, 9(10):1475-90
Torgersen ML, Engedal N, Boe SO, Hokland P, Simonsen A. Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells. Blood, 2013. 122(14):2467-76
Regulation of autophagy by calcium perturbation and ER stress / the unfolded protein response (UPR) in malignant and nonmalignant cells.
In this project we are unravelling how changes in the intracellular calcium balance and the so-called "unfolded protein response" (UPR), which is unleashed by endoplasmic reticulum (ER) stress, are regulating autophagy. Intracellular calcium perturbation and UPR are often interrelated, and both are strongly implicated in cancer as well as other diseases. We have found that calcium pump inhibitors such as the plant compound thapsigargin blocks autophagy (Engedal et al., 2013, Autophagy 9(10):1475-90). Now we are following up on these findings. In collaboration with Poul Nissen and Jesper Vuust Møller (Århus University and DANDRITE) and Søren Brøgger Christensen (University of Copenhagen), we are investigating the actions of various thapsigargin analogues, which affect the ER calcium pump in different ways. Some of these analogs constitute the active ingredients of therapeutic cancer prodrugs that are currently at the phase of clinical trials in human cancer patients. Main participants: Paula Szalai, Morten Luhr, Frank Sætre, Nikolai Engedal.
In another, major part of the project, we are studying other UPR-inducers, which do not provoke the same strong calcium perturbation as thapsigargin, and which activate autophagy. We are deciphering the UPR signalling pathways that control autophagy, and aim to identify specific downstream mediators of UPR-induced autophagy.
Main participants: Morten Luhr, Paula Szalai, Frank Sætre, Nikolai Engedal.
Intersections between autophagy and apoptosis under ER stress conditions, and mechanisms of cell death induced by therapeutically relevant anti-cancer drugs.
We aim to dissect how the autophagic process and autophagy machinery components affect and intersect with apoptotic pathways under various ER stress conditions. To this end, we amongst others genetically interfere with various components of the autophagy machinery and correlate effects on apoptotic pathways and autophagic activity, respectively. Moreover, we are deciphering the roles of calcium perturbation and different UPR signaling pathways in the induction of cell death – with a strong focus on that induced by thapsigargin and therapeutically relevant thapsigargin analogs.
Main participants: Paula Szalai, Morten Luhr, Frank Sætre, Nikolai Engedal.
The role of autophagy-related genes (Atgs) in basal, starvation, and stress-induced bulk autophagy in mammalian cells
One of the main strengths of our lab is our heavy investment in methodological approaches to quantitatively measure bulk autophagic activity with functional assays, instead of relying on surrogate markers. Using this approach, we recently made the surprising finding that bulk autophagy is independent of LC3 proteins, whereas the related, and less studied GABARAP family is strictly required (Szalai et al., 2015, ECR, 333(1):21-38). This is finding is of major importance, since most studies of autophagy in mammalian cells are using LC3 as the major or only marker to measure autophagy. Moreover, it demonstrates that there is still much to learn about the roles of the various Atgs in mammalian autophagy. In parallel to the projects described above, we are uncovering the requirements for various Atgs in bulk autophagic sequestration and degradation activity in different cell lines and under different conditions. In particular, RNAi-mediated approaches are used to identify gene products whose expression levels are strong determinants of the bulk autophagic process. This is currently a side-project, which we aim to strengthen.
Main participants: Morten Luhr, Paula Szalai, Frank Sætre, Nikolai Engedal.
Regulation of autophagosome completion
Our previous findings strongly suggest that perturbation of intracellular calcium levels blocks autophagy at a late stage in autophagosome formation (Engedal et al., 2013, Autophagy 9(10):1475-90). Moreover, initial block-release experiments with thapsigargin and 3-methyl adenine indicated that PI3-kinases are also required for a late step in autophagosome formation (Saetre et al. 2015, FEBS J, 282(11):2202-14). Exploring various approaches, we have now established a block-release protocol in cell lines that can be used to specifically study the autophagosome completion process. This is currently a side-project, which we aim to strengthen.
Main participants: Paula Szalai (previous work), Frank Sætre, Per Seglen, Nikolai Engedal.
A novel form of autophagy identified in primary rat hepatocytes
In this project we are studying a novel form of autophagy identified by Per Seglen under starvation-conditions in primary rat hepatocytes. This form of autophagy sequesters cytosolic proteins in a manner that, as opposed to conventional autophagy, is completely independent of calcium perturbation as well as of PI3-kinases. Interestingly, our results so far indicate that this form of autophagy is shut down in cancer cells.
Main participants: Per Seglen, Frank Sætre, Nikolai Engedal.
Our research is, or has recently been, funded by:
- The Nansen Foundation
- The Legacy in the memory of Henrik Homan
- The Anders Jahre Foundation
- Family Blix' Foundation
- Poul Nissen, Danish Research Institute of Translational Neuroscience, Denmark
- Jesper Vuust Møller, University of Aarhus, Denmark
- Søren Brøgger Christensen, University of Copenhagen, Denmark
- Sun Nyunt Wai, University of Umeå, Sweden
- Jan Parys, University of Leuven, Belgium
- Joseph D. Mancias, Dana-Farber Cancer Institute, Harvard Medical School, USA
- Terje Johansen, The Arctic University of Norway
- Oddmund Bakke, University of Oslo, Norway
- Cinzia Progida, University of Oslo, Norway
- Harald Stenmark, Institute of Cancer Research, Oslo University Hospital, Norway
Per O. Seglen awarded the King Olav V's cancer research prize for 2017:
- UiO Medical Faculty: Per Seglen receives King Olav V Prize for Cancer Research
- Kreftforeningen: Kong Olav Vs kreftforskningspris 2017 (in Norwegian
In-depth research profile:
Paula Szalai wins poster prize
Congratulations to Paula Szalai who won the prize for the best poster at the first ever Nordic Autophagy Society Conference in Sigtuna, Sweden, which took place over 30 October-1 November 2017. The prize of 200EUR was sponsored by the FEBS (Federation of European Biochemical Societies) Journal.