Prof. Dr. Georg Häcker

We are in particular interested how mammalian cells respond to the challenges of infection, both when directly exposed to microbial agents and during a more complex immune response. A major line of work analyses the role of cell death systems (apoptosis, also necrosis) and their molecular connections to immune signaling pathways. Although apoptosis is a common response to changes in the environment (including infections), very little molecular information is available on the question how these changes are interpreted as a signal to undergo apoptosis. One important hub consists of the mitochondrial platform of Bcl-2-family proteins, and we focus on the question of how the Bcl-2-family triggers of apoptosis (BH3-only proteins) are activated. Approaches include definition of active submolecular domains and of relevant partnering and the definition of minimal requirements in reconstitution systems. An intriguing set of apoptosis regulators are the Inhibitor of Apoptosis Proteins (IAPs). These proteins act at least in part as ubiquitin ligases and are turning out to be critical regulators of the activation of several defence systems, notably NF-kappa B, apoptosis and necrosis. We are investigating the molecular background and immunological consequences of manipulation of IAPs. In viral infections the apoptotic death of an infected cell is part of the cell-autonomous defence. How a cell makes the decision to undergo apoptosis and how viruses try to keep the cell alive on a molecular level is another focus of interest. Neutrophil granulocytes (neutrophils) are essential cells of first-line immunity. As the investigation of neutrophils is technically challenging we have established an experimental system that permits the generation of neutrophils from conditionally transformed progenitor cells. These cells can be experimentally easily manipulated and we are utilizing this system to analyse regulation of survival vs. turnover as well as functional defects in neutrophils. One line of work focuses on the interaction with the obligate intracellular bacteria, Chlamydiae, and the host cell. Here the focus of our studies lies on the questions of how Chlamydia escapes the host cell’s defence systems and how Chlamydia acquires necessary nutrient molecules from the host cell. The inflammatory and immune responses during chlamydial infection and during GvHD are further topics we are investigating.

10 selected publications:

• A non-death function of the mitochondrial apoptosis apparatus in immunity.
  Brokatzky D, Dörflinger B, Haimovici A, Weber A, Kirschnek S, Vier J, Metz A, Henschel J, Steinfeldt T, Gentle IE, Häcker G.
  EMBO J. 2019 Apr 12. pii: e2018100907.
• Neutrophils provide cellular communication between ileum and mesenteric lymph nodes at graft-versus-host disease onset.
  Hülsdünker J, Ottmüller KJ, Neeff HP, Koyama M, Gao Z, Thomas OS, Follo M, Al-Ahmad A, Prinz G, Duquesne S, Dierbach H, Kirschnek S, Lämmermann T, Blaser MJ, Fife BT, Blazar BR, Beilhack A, Hill GR, Häcker G, Zeiser R (2018).
  Blood. 131(16):1858-1869.
• Dynein light chain 1 induces assembly of large Bim complexes on mitochondria that stabilize Mcl-1 and regulate apoptosis.
  Singh PK, Roukounakis A, Frank DO, Kirschnek S, Das KK, Neumann S, Madl J, Römer W, Zorzin C, Borner C, Haimovici A, Garcia-Saez A, Weber A, Häcker G (2017).
  Genes Dev. 31(17):1754-1769.
• The deubiquitinase Usp27x stabilizes the BH3-only protein Bim and enhances apoptosis.
  Weber A, Heinlein M, Dengjel J, Alber C, Singh PK, Häcker G (2016).
  EMBO Rep. 17(5):724-38.
• Neutrophil granulocytes recruited upon translocation of intestinal commensal bacteria enhance graft-versus-host disease via local tissue damage. 
  Schwab L, Goroncy L, Palaniyandi S, Gautam S, Triantafyllopoulou A, Mocsai A, Reichardt W, Karlsson F J, Radhakrishnan S V,  Hanke K, Schmitt-Graeff A, Freudenberg M, von Loewenich F D, Wolf P, Leonhardt F, Baxan N, Pfeifer D, Schmah O, Schönle A, Martin S F, Mertelsmann R, Duyster J, Finke J, Prinz M, Henneke P, Häcker H, Hildebrandt G C*, Häcker G.*, Zeiser R* (2014)
  Nat Med. 20(6):648-54.
  * Equal contribution
• BH3-only proteins are tail-anchored in the outer mitochondrial membrane and can initiate the activation of Bax.
  Wilfling F, Weber A, Potthoff S, Vögtle FN, Meisinger C, Paschen SA, Häcker G (2012).
  Cell Death Differ. 19(8):1328-36.
• Induction of Noxa-mediated apoptosis by Modified Vaccinia Virus Ankara depends on viral recognition by cytosolic helicases, leading to IRF-3/IFN-ß-dependent induction of pro-apoptotic Noxa.
  Eitz Ferrer P, Potthoff S,  Kirschnek S, Gasteiger G, Kastenmüller W, Ludwig H, Paschen S, Villunger A, Sutter G, Drexler I, Häcker G (2011).
  PLoS Path., 7(6):e1002083. Epub 2011 Jun 16.
• Bim_S Induced apoptosis requires mitochondrial localization but not interaction with anti-apoptotic Bcl-2 proteins.
  Weber A, Paschen SA, Heger K, Wilfling F, Frankenberg T, Bauerschmitt H, Seiffert BM, Kirschnek S, Wagner H, Häcker G (2007).
  J Cell Biol 177(4):625-36.
• The NF-kappaB regulator Bcl-3 and the BH3-only proteins Bim and Puma control the death of activated T cells.
  Bauer A, Villunger A, Labi V, Fischer SF, Erlacher M, Strasser A, Wagner H,  Schmid RM, Häcker G (2006).
  Proc Natl Acad Sci USA, 103:10979-84.
• Specificity in TLR Signaling: Activation of the Interferon Response Depends on TRAF3.
  Häcker H, Redecke V, Blagoev B, Kratchmarova I, Wang G, Kamps MP, Saha SK, Oganesyan G, Raz E, Wagner H, Häcker G, Mann M, Cheng G, Karin M (2006).
  Nature 439:204-207.