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In order for our cells to stay healthy and functional, they must identify and dispose of damaged and harmful substances. Autophagy (from the Greek word for self-eating) is a process that cells employ to remove this material so that it can be replaced with new and functional parts. During autophagy cellular substances become engulfed by vesicles, the autophagosomes. How autophagosomes form de novo around their cargos is fascinating, yet still enigmatic. At the end of their biogenesis the vesicles fuse with cellular compartments called lysosomes which degrade the cargo. Autophagy was shown to target a variety of components including protein aggregates, organelles and even invading pathogens after they enter the cytoplasm. Not surprisingly, defects in autophagy have been associated with numerous diseases such as neurodegeneration, cancer and uncontrolled infections.
Past research has identified a plethora of factors that are required for autophagy. However, how these factors act together in order to couple the capturing of the cellular material destined for degradation with the formation of autophagosomes is not well understood. Thus, the challenge now is to assign functions and mechanisms to these factors in order to gain a better understanding of how they work together to enable autophagy. We are a multidisciplinary team that focuses on bottom-up approaches to understand how cells form autophagosomes. To this end, we employ biochemical reconstitution, cell biology, light and electron microscopy as well as structural biology approaches. Our long-term goal is to reconstitute autophagy in vitro and compare the outcome to its working in cells. When those two match up we will understand how cells dispose harmful material.
Sascha Martens obtained his Diploma and Doctoral degrees from the University of Cologne in Germany. For his postdoctoral training he moved to the MRC Laboratory of Molecular Biology in Cambridge, UK. In 2009 he established his independent laboratory at the Max Perutz Labs.
During clearance of misfolded, ubiquitinated proteins these cargoes need be recognized and collected within larger condensates followed by the recruitment of the autophagy machinery to mediate their degradation. Employing a blend of reconstitution experiment and cell biological approaches, we have dissected the interplay and individual contributions of the p62, NBR1 and TAX1BP1 cargo receptors during this process. We found that p62 is the main driver of cargo condensation. NBR1 promotes condensate formation by equipping the p62-NBR1 hetero- oligomeric complex with a high-affinity UBA domain. Additionally, NBR1 recruits TAX1BP1 to the ubiquitin condensates formed by p62. While all three receptors interact with FIP200, TAX1BP1 is the main driver of FIP200 recruitment and thus the autophagic degradation of p62–ubiquitin condensates. In summary, our study defines the roles of all three receptors in the selective autophagy of ubiquitin condensates.
See our publication in Nature Communications
The model was created by Dorotea Fracchiolla (https://my-art-science.com/)
To stay healthy, our cells must constantly dispose of harmful material. Autophagy, or self-eating, is an important mechanism to ensure the clearance of bulky material. Such material is enwrapped by cellular membranes to form autophagosomes, the contents of which are then degraded. The formation of autophagosomes is a complicated process involving a large number of factors. How they act together in this process is still enigmatic. We recapitulated the initial steps of autophagosome formation using purified autophagy factors from yeast. This approach elucidated some of the organizational principles of the autophagy machinery during the assembly of autophagosomes.
See our publication in Science.
See also Verena’s fantastic video.
Together with colleagues from the University of Berkeley (USA) we have reconstituted the activity of key proteins involved in the growth of autophagosome precursors, a process essential for encapsulating cellular components targeted for degradation and recycling. Our results reveal a previously unknown positive feedback loop and activation mechanism that help explain how the autophagy machinery rapidly generates the autophagosomal membrane. The study is published in the Journal of Cell Biology.
Watch Dorotea's amazing animation: https://www.youtube.com/watch?v=soWx_tuJm_g
We show that the C-terminal domain of FIP200 binds to the p62 cargo receptor promoting the recruitment and activation of the autophagy machinery at ubiquitin condensates. This in turn results in their sequestration within autophagosomes and eventually degradation of the condensates. Structural studies showed that the C-terminal domain of FIP200 is shaped like a claw. This study is published in Molecular Cell.
We found that in vitro the autophagy receptor p62 and ubiquitinated substrates spontaneously phase separate into clusters. Mechanistically, this is based on the crosslinking of p62 filaments by the substrates. We further uncover multiple modes of regulation of the clustering reaction that suggest how this process can be integrated into general proteostasis. This study is published in the EMBO Journal.
We discovered that the yeast cargo receptor Atg19 directly interacts with the E3-like Atg12–Atg5-Atg16 complex via its LIR motifs. In a fully reconstituted system we show that these interactions are sufficient to mediate Atg8 conjugation at the cargo. The recruitment of the E3-like complex to cargo may be conserved since we show that also human cargo receptors bind the ATG5 protein. This study is published in eLife.
We show that the Atg19 cargo receptor contains multiple interaction sites for the Atg8 protein. Atg8 proteins decorate the autophagosomal membrane and collectively these multiple interaction sites for Atg8 bend the membrane around autophagic cargo material. The close apposition of the membrane and the cargo excludes non-cargo material from its delivery into the lysosomal system. This study is published in Nature Cell Biology.
Reconstitution defines the roles of p62, NBR1 and TAX1BP1 in ubiquitin condensate formation and autophagy initiation
Turco, Eleonora; Savova, Adriana; Gere, Flora; Ferrari, Luca; Romanov, Julia; Schuschnig, Martina; Martens, Sascha
Reconstitution of autophagosome nucleation defines Atg9 vesicles as seeds for membrane formation.
Sawa-Makarska, Justyna; Baumann, Verena; Coudevylle, Nicolas; von Bülow, Sören; Nogellova, Veronika; Abert, Christine; Schuschnig, Martina; Graef, Martin; Hummer, Gerhard; Martens, Sascha
A PI3K-WIPI2 positive feedback loop allosterically activates LC3 lipidation in autophagy.
Fracchiolla, Dorotea; Chang, Chunmei; Hurley, James H; Martens, Sascha
FIP200 Claw Domain Binding to p62 Promotes Autophagosome Formation at Ubiquitin Condensates.
Turco, Eleonora; Witt, Marie; Abert, Christine; Bock-Bierbaum, Tobias; Su, Ming-Yuan; Trapannone, Riccardo; Sztacho, Martin; Danieli, Alberto; Shi, Xiaoshan; Zaffagnini, Gabriele; Gamper, Annamaria; Schuschnig, Martina; Fracchiolla, Dorotea; Bernklau, Daniel; Romanov, Julia; Hartl, Markus; Hurley, James H; Daumke, Oliver; Martens, Sascha
p62 filaments capture and present ubiquitinated cargos for autophagy.
Zaffagnini, Gabriele; Savova, Adriana; Danieli, Alberto; Romanov, Julia; Tremel, Shirley; Ebner, Michael; Peterbauer, Thomas; Sztacho, Martin; Trapannone, Riccardo; Tarafder, Abul K; Sachse, Carsten; Martens, Sascha
Mechanism of cargo-directed Atg8 conjugation during selective autophagy
Fracchiolla, D., Sawa-Makarska, J., Zens, B., de Ruiter, A., Zaffagnini,G., Brezovich, A., Romanov, J., Runggatscher, K., Kraft,C., Zagrovic, B. and Sascha Martens
Oligomerization of p62 allows for selection of ubiquitinated cargo and isolation membrane during selective autophagy.
Wurzer, Bettina; Zaffagnini, Gabriele; Fracchiolla, Dorotea; Turco, Eleonora; Abert, Christine; Romanov, Julia; Martens, Sascha
Cargo binding to Atg19 unmasks additional Atg8 binding sites to mediate membrane-cargo apposition during selective autophagy.
Sawa-Makarska, Justyna; Abert, Christine; Romanov, Julia; Zens, Bettina; Ibiricu, Iosune; Martens, Sascha
Mechanism and functions of membrane binding by the Atg5-Atg12/Atg16 complex during autophagosome formation.
Romanov, Julia; Walczak, Marta; Ibiricu, Iosune; Schüchner, Stefan; Ogris, Egon; Kraft, Claudine; Martens, Sascha
We have been awarded an ASAP Grant in 2020 to study the mechansims of mitophagy together with the Hurley (coordinator), Park, Holzbaur, Lazarou and Hummer labs.
Sascha Martens was awarded the Program Grant from HFSP for a collaborative project together with scientists from Germany, USA and Japan.
Sascha Martens is awardee of a "Consolidator Grant" from the European Research Council ERC.
The Martens Lab was awarded FWF Stand Alone Grants (P25546-B20, P27799-B20, P30401-B21, P32814-B and P35061-B) to support our research on autophagy.
Sascha Martens joins the network of EMBO Young Investigators.
Sascha Martens is awardee of a "Starting Independent Researcher Grant" from the European Research Council ERC.
Sascha Martens has been elected member of the "Junge Kurie" of the Austrian Academy of Sciences in April 2011