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HORMA domain proteins in Autophagy initiation

dc.contributor.advisorFaesen, Alex Caspar Dr.
dc.contributor.authorLugarini, Francesca
dc.titleHORMA domain proteins in Autophagy initiationde
dc.contributor.refereeFaesen, Alex Caspar Dr.
dc.description.abstractengThe autophagic pathway is an evolutionarily conserved strategy among eukaryotic cells for maintaining cell homeostasis at the basal level and during stressful conditions. It removes protein aggregates, damaged organelles, and pathogens. In particular, it is necessary for balancing energy sources at crucial stages of normal development and tumor progression, and it is upregulated in reaction to starvation, DNA damage, hypoxia, amino acid, and ATP deficiency (Levine and Klionsky, 2004; Levine and Kroemer, 2008; Glick, Barth and Macleod, 2010; Feng et al., 2014; Hurley and Young, 2017; Mizushima, 2018). Since autophagy is quality maintenance and a defensive mechanism, an unbalanced modulation of the pathway can be harmful and, therefore, requires stringent regulation. At the ER contacts site, the ULK1 complex, as well as other proteins like ATG9, the lipid transfer complex ATG2-WIPI and the PI3KC colocalize to initiate autophagy (Mari et al., 2010; Obara and Ohsumi, 2011; S. W. Suzuki et al., 2015a; Yamamoto et al., 2016; Chowdhury et al., 2018; Noda, 2021a). However, it is not clear how all these components coalesce to form and progress the expansion of the autophagosome. Inside the ULK1 complex, ATG13 and ATG101, dimerize through their HORMA structure (Qi et al., 2015; Suzuki et al., 2015), similarly to MAD2, the most described HORMA (Luo et al., 2002; Sironi et al., 2002). These proteins are largely uncharacterized in their HORMA-related function in autophagy initiation. In this work, we investigated the impact of the HORMA domain structure of ATG13 and ATG101 in the recruitment of some of the autophagy initiation subcomplexes (Jao et al., 2013; S. W. Suzuki et al., 2015; Kim et al., 2018; Park et al., 2019; Kannangara et al., 2021) by an in vitro biochemical reconstitution approach using purified proteins. We show that ATG13 and ATG101 directly interact with the lipid scramblase ATG9 in an incredibly slow fashion and that the complex formation is accelerated by a conformationally-sensitive dimerization of ATG101-ATG13. We also assessed that ATG13-ATG9-ATG101 form a super-complex with other components of autophagy initiation and propose that ATG13-ATG101 interaction to ATG9 is the rate-limiting factor that regulates assembly at the ER contact sites of this super-complex involved in autophagosome biogenesis and
dc.contributor.coRefereeThumm, Michael Prof. Dr.
dc.contributor.thirdRefereeStein, Alexander Dr.
dc.contributor.thirdRefereeLorenz, Sonja Dr.
dc.contributor.thirdRefereeUrlaub, Henning Prof. Dr.
dc.contributor.thirdRefereeFernández-Busnadiego, Rubén Prof. Dr.
dc.subject.engBiochemical reconstitutionde
dc.subject.engInitiation complexde
dc.subject.engER contacts sitesde
dc.affiliation.instituteBiologische Fakultät für Biologie und Psychologiede
dc.subject.gokfullBiologie (PPN619462639)de
dc.notes.confirmationsentConfirmation sent 2022-08-01T13:45:01de

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