The main focus areas of the research group are; 1) characterization of the membrane remodeling and trafficking events required for autophagosome formation, 2) identification of the molecular machinery involved in selection of cargo for degradation by autophagy and 3) understanding the role of autophagy in fusion-protein-associated leukemia and protein aggregate-associated neurodegenerative disease.
We have made the following important contributions to the field:
- The PX-BAR protein SNX18 was identified as a positive regulator of autophagosome formation through its ability to tubulate recycling endosome membranes and provide input to the forming phagophore (Knævelsrud et al. J Cell Biol. 2013)
- The large PI3P-binding protein ALFY (autophagy-linked FYVE) was found to be recruited to protein inclusions and to scaffold a complex containing the ubiquitin-binding autophagy receptor p62, as well as the autophagic effectors Atg5 and LC3. We found that depletion of ALFY inhibited clearance of huntingtin aggregates, whereas ALFY over-expression diminished inclusion number and lead to neuroprotection in a neuronal and Drosophila model of Huntington's disease (Filimonenko et al, Mol Cell, 2010).
- We have shown that autophagic degradation regulates both the basal turnover and the therapy-induced elimination of the aggregate-prone oncoprotein PML/RARA, associated with acute promyelocytic leukemia (APL). This study also revealed an important role of autophagy in promoting granulocytic differentiation of APL cells (Isakson et al, Blood 2010). However, this does not seem to be a general feature of leukemic fusion oncoproteins, as we recently found that AML1-ETO, the most frequently occurring acute myeloid leukemia (AML) fusion protein, is not an autophagy substrate. Rather we demonstrate a clear pro-survival role of autophagy in this AML subtype and that addition of autophagy inhibitors in the treatment regimen might be beneficial.