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Institut für Medizinische Mikrobiologie und Hygiene

Apoptosis

Apoptosis is one of the general reaction patterns that human cells have when being exposed to stimuli from the outside, or stimuli building up inside for instance from ongoing metabolism. Human cells differ greatly in their propensity to undergo apoptosis but this difference is actually only poorly understood. Once a cell has decided to die by apoptosis, a specialised signalling pathway is activated, which often involves a step of mitochondrial activity. The mitochondrial proteins cytochrome c and Smac are released, and proteases of the caspase-family are activated in the cytosol. Caspase-activity causes the typical signs and features of apoptosis.

How mitochondria are induced to release the proteins is still not well understood. This step is coordinated by the Bcl-2-family of mitochondrial proteins, which contain both pro- and anti-apoptotic members. In recent times, most of our work has been directed at trying to understand how the Bcl-2-family gets started. The first proteins here are the BH3-only proteins, such as Bim and Bmf. We have been looking at the role and regulation of some of these proteins, for instance in the activation of Bax/Bak (the effectors of cytochrome c-release) and their role in the survival of haematopoietic cells such as neutrophil granulocytes. We have also investigated their regulation through ubiquitination (especially Bim) (Weber et al., 2016), have found that they are inserted into the outer mitochondrial membrane with their C-terminus (Weber et al., 2007; Wilfling et al., 2012) and have recently discovered unexpected large protein complexes on mitochondrial where Bcl-2-family proteins (Singh et al., 2017; Singh et al., 2019), and especially BH3-only proteins, are coordinated by a small protein called dynein light chain. We are currently trying to understand the regulation of these complexes.

References

Singh, P.K., Roukounakis, A., Frank, D.O., Kirschnek, S., Das, K.K., Neumann, S., Madl, J., Romer, W., Zorzin, C., Borner, C., et al. (2017). Dynein light chain 1 induces assembly of large Bim complexes on mitochondria that stabilize Mcl-1 and regulate apoptosis. Genes & development 31, 1754-1769.

Singh, P.K., Roukounakis, A., Weber, A., Das, K.K., Sohm, B., Villunger, A., Garcia-Saez, A.J., and Hacker, G. (2019). Dynein light chain binding determines complex formation and posttranslational stability of the Bcl-2 family members Bmf and Bim. Cell death and differentiation.

Weber, A., Heinlein, M., Dengjel, J., Alber, C., Singh, P.K., and Hacker, G. (2016). The deubiquitinase Usp27x stabilizes the BH3-only protein Bim and enhances apoptosis. EMBO reports.

Weber, A., Paschen, S.A., Heger, K., Wilfling, F., Frankenberg, T., Bauerschmitt, H., Seiffert, B.M., Kirschnek, S., Wagner, H., and Hacker, G. (2007). BimS-induced apoptosis requires mitochondrial localization but not interaction with anti-apoptotic Bcl-2 proteins. The Journal of cell biology 177, 625-636.

Wilfling, F., Weber, A., Potthoff, S., Vogtle, F.N., Meisinger, C., Paschen, S.A., and Hacker, G. (2012). BH3-only proteins are tail-anchored in the outer mitochondrial membrane and can initiate the activation of Bax. Cell death and differentiation 19, 1328-1336.

Institut für Medizinische Mikrobiologie und Hygiene

Hermann-Herder-Str. 11
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Ärztlicher Direktor
Prof. Dr. Georg Häcker
E-mail: georg.haecker@uniklinik-freiburg.de

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