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Molekulare Medizin und Zellforschung - AG Borner

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Research interests


Programmed cell death (PCD) and its predominant phenotype, apoptosis, is essential to ensure and maintain the life of multicellular organisms. If it is absent or dysregulated, embryogenesis is aborted or impaired, tissues homeostasis is interrupted and damaged or used-up cells are not eliminated. Thus, defaults of apoptosis are implicated in numerous pathological conditions, ranging from degenerative disorders to autoimmunity and cancer.
Apoptosis can either be triggered by so called "death receptors" on the cell surface or by various forms of stress, such as a lack of cytokine/growth factor support and diverse types of cellular damage. These apoptotic stimuli provoke, in one way or the other, the activation of a set of previously inactive death proteases, the caspases, which, via an amplifying proteolytic cascade cleave hundreds of substrates to dismantle the cell. During periods of stress, the cell's decision to launch the cell death program relies primarily on the Bcl-2 family of proteins. This family consists of Bcl-2-like relatives that promote survival, and two structurally distinct relatives (Bax-like and BH3-only) which instead elicit cell death. Through protein-protein interactions, these opposing members integrate survival and death signals from the environment to determine whether to condemn the cell to its death demise or to endow it with the capacity to resist and survive.
Bcl-2 family members mainly control the permeability of the outer mitochondrial membrane (MOMP). In response to apoptotic stimuli one or several BH3-only proteins are activated by either transcriptional induction (Bim, Puma, Noxa, Bmf), posttranslational modification (mainly phosphorylation) (Bim, Bad) or proteolytic cleavage (Bid to tBid) and then function in two ways. 1) as "direct activators" of Bax and Bak. Hereby Bim, tBid and evtl. also Puma translocate to mitochondria and trigger within the outer mitochondrial membrane the di- or oligomerization of Bax/Bak which finally leads to pore formation and the release of cytochrome c and other apoptogenic factors which activate caspase-dependent and -independent death signaling pathways.  2) as "sensitizers/derepressors" of Bax/Bak activation. In this case the BH3-onlies bind, via their BH3-domain, with different specificities to the hydrophobic pocket of Bcl-2-like and thereby either release already activated Bax/Bak that have been sequestered at the pocket, or they neutralize all Bcl-2-like survival factors, allowing additional Bim, tBid and Puma to more effectively activate Bax/Bak.
In addition to interactions among the members of the Bcl-2 family, other binding partners seem to be part of Bcl-2 complexes in order to fine-tune MOMP. Moreover, Bcl-2 family have been implicated in other cellular processes such as cell cycle regulation, mitochondrial fission/fusion, autophagy, etc. and these processes require additional binding partners. It is therefore crucial to identify these proteins and determine their modes of action. Another unresolved issue is how BH3-only proteins are activated by posttranslational mechanisms. Recent evidence suggests that most BH3-only proteins are already quite abundant and present within high molecular weight protein complexes (up to 600 kD) in healthy cells. So, which modification(s) activate(s) BH3-onlies and what is the consequence of this activation? Is activation mainly achieved through phosphorylation? At which sites do these phosphorylations occur? And how do they influence the affinities of the BH3-only proteins for Bcl-2-like survival factors and/or Bax/Bak? Finally, it is yet unclear how BH3-only proteins cooperate with each other to effectively induce MOMP. We attempt to get further insights into these mechanisms by studying various apoptosis systems, including those induced by viruses and fungal toxins.

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The following projects are currently running in the lab:

1.    Identify novel proteins that interact with Bcl-xL, Bcl-2, Bax and Bak in healthy and apoptotic cells, validate their interactions under physiological conditions and determine the significance of these interactions for apoptosis and other cellular processes governed by Bcl-2 family members, such as the regulation of the cell cycle, autophagy, mitochondrial fission/fusion, etc. (funded by BIOSS-2)

2.    Understand the apoptotic signaling pathway induced by Semliki Forest alphavirus and other RNA and DNA viruses. We recently published that SFV induces both caspase-3 activation in two parallel ways, (i) via Bax/Bak activation and (ii) via the recruitment of caspase-8 to mitochondria by the innate immune signaling mediator MAVS which then activates caspase-8 and triggers further caspase-3 processing (El Maadidi et al., J. Immunol. 192, 1171-1183, 2014). We like to identify the adapter of the MAVS/caspase-8 complex (it is not FADD!), if this novel way of caspase-8 activation and caspase-3 processing is also used by other apoptotic stimuli/viruses and which BH3-only protein activates Bax/Bak in response to SFV infection.

3.    Understand the apoptotic signaling pathway induced by the virulence factor gliotoxin (GT) from the fungus Aspergillus fumigatus (A.f). This toxin is the cause for the opportunistic disease Invasive Aspergillosis (IA) which produces lethal pulmonary infections in immunodeficient patients. GT induces Bak-mediated apoptosis of epithelial cells by JNK1/2-mediated phosphorylation of Bim at three sites S100, T112 and S114 (Geissler et al., Cell Death Differ. 20, 1317-1329, 2013). We showed that these phosphorylations increase the affinity of Bim for Bcl-2/xL/Mcl-1 binding. We now want to identify the cellular target of GT and unravel how this target activates JNK1/2. Since the fungus and GT also regulate the innate immune response, we are also investigating the disease in mice after infection with A.f. in vivo. The goal is to find new therapeutics that break the resistance of many IA patients to antifungal treatments.

4.    Identify novel phosphorylation sites and binding partners of Bim and Puma and determine their role in regulating the pro-apoptotic activities of these two proteins (funded by FOR2036 of the DFG)


5.    Understand how TNF-alpha sensitizes hepatocytes to FasL-induced apoptosis and determine the relevance of this sensitization in mouse liver damage models in vivo. We obtained evidence that the TNF-alpha sensitization is through Bim (Schmich et al., Hepatology, 53, 282-292, 2011) but we do not know yet the mechanism(s) by which Bim is activated. In addition, we want to identify under which liver damage conditions (alcohol, LPS, virus infection, NASH, etc.) TNF-alpha and/or FasL play crucial roles for hepatotoxicity and by which molecular mechanism(s) they trigger apoptosis and/or necrosis/necroptosis in vivo (funded by the BMBF, Virtual Liver Network (VLN), http://www.virtual-liver.de/)

6. Identify the role of apoptosis and/or autophagy in the development of polycystic kidney disease (PKD) with a focus on the mechanism by which Bcl-2 family members influence PKD formation in a mouse model of slowly progressing disease (funded by SFB 1140 (KIDGEM) of the DFG)

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