Cell death represents a central component of the immune system and its alteration has been intimately associated with human diseases. Whereas initial studies considered cell death as a quantitative counterbalance of cell proliferation, it is increasingly evident that dying cells efficiently coordinate the fade of the surrounding tissue by emitting different factors. Different modes of cellular death processes have been identified that involve distinct cellular death machineries and release a battery of different mediators. These can ultimately cause beneficial or detrimental tissue outcomes. The molecular link between cellular death and inflammatory signalling is currently considered as a fundamental process governing tissue functionality and represents the central objective of our research group.

Although different cellular death pathways are executed with molecularly distinct death machineries, recent evidence including our own results indicated that these pathways are molecularly interlinked and provide a dynamic plasticity in cellular death and inflammatory responses. The molecular link between different cellular death modalities and inflammation represents the central objective of our research group. We are, in particular, investigating the role of caspases, inhibitor of apoptosis proteins (IAPs) and mitochondria as intimately linked signalling components of both cell death and inflammation. By modelling human diseases in appropriate in vivo model-systems, we will discover the physiological roles of these processes in tissue homeostasis and their contribution to pathophysiology of human diseases. The molecular knowledge obtained will be exploited to design novel therapeutic protocols for human diseases by targeting cellular death pathways.

Selected original publications (last 10 years)

Albert MC, Brinkmann K, Pokrzywa W, Günther SD, Krönke M, Hoppe T*, Kashkar H*.
CHIP ubiquitylates NOXA and induces its lysosomal degradation in response to DNA damage. Cell Death Dis. 2020, 11(9):740 *Corresponding author

Schiffmann LM, Werthenbach JP, Heintges-Kleinhofer F, Seeger JM, Fritsch M, Günther SD, Willenborg S, Brodesser S, Lucas C, Jüngst C, Albert MC, Schorn F, Witt A, Moraes CT, Bruns C, Pasparakis M, Krönke M, Eming SA, Coutelle O, Kashkar H.
Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth. Nat. Commun. 2020, 11(1):3653

Günther SD, Fritsch M, Seeger JM, Schiffmann LM, Snipas SJ, Coutelle M, Kufer TA, Higgins PG, Hornung V, Bernardini ML, Höning S, Krönke M, Salvesen GS, Kashkar H.
Cytosolic Gram-negative bacteria prevent apoptosis by inhibition of effector caspases through lipopolysaccharide. Nat. Microbiol. 2020, 5(2):354–367

Fritsch M, Günther SD, Schwarzer R, Albert MC, Schorn F, Werthenbach JP, Schiffmann LM, Stair N, Stocks H, Seeger JM, Lamkanfi M, Krönke M, Pasparakis M, Kashkar H.
Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature 2019, 575(7784):683-687

Schiffmann LM, Fritsch M, Gebauer F, Günther SD, Stair NR, Seeger JM, Thangarajah F, Dieplinger G, Bludau M, Alakus H, Göbel H, Quaas A, Zander T, Hilberg F, Bruns CJ, Kashkar H*, Coutelle O*.
Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer. Br J Cancer. 2019, 120(1):69-78 *equal contribution

Knittel G*, Liedgens P*, Korovkina D*, Seeger JM*, Al-Baldawi Y, Al-Maarri M, Fritz C, Vlantis K, Bezhanova S, Scheel AH, Wolz OO, Reimann M, Möller P, López C, Schlesner M, Lohneis P, Weber AN, Trümper L, Consortium IM, Staudt LM, Ortmann M, Pasparakis M, Siebert R, Schmitt CA, Klatt AR, Wunderlich FT, Schäfer SC, Persigehl T, Montesinos-Rongen M, Odenthal M, Büttner R, Frenzel LP^§, Kashkar H^§, Reinhardt HC^§.
B cell-specific conditional expression of Myd88^p.L252P leads to the development of diffuse large B cell lymphoma in mice. Blood 2016, 127(22):2732-41. * ^{and §} equal contribution

Witt A, Seeger JM, Coutelle O, Zigrino P, Broxtermann P, Andree M, Brinkmann K, Jüngst C, Schauss AC, Schüll S, Wohlleber D, Knolle P, Krönke M, Mauch C, Kashkar H.
IAP antagonization induces inflammatory destruction of vascular endothelium EMBO Rep. 2015, 16:719-727

Schüll S, Günther SD, Brodesser S, Seeger JM, Tosetti B, Wiegmann K, Pongratz C, Diaz F, Witt A, Andree M, Brinkmann K, Krönke M, Wiesner RJ, Kashkar H.
Cytochrome c oxidase deficiency accelerates mitochondrial apoptosis by activating ceramide synthase 6. Cell Death Dis. 2015, 6:e1691

Coutelle O, Schiffmann LM, Liwschitz M, Brunold M, Goede V, Hallek M, Kashkar H*, Hacker UT*.
Dual targeting of Angiopoetin-2 and VEGF potentiates effective vascular normalization without inducing empty basement membrane sleeves in xenograft tumors. Br J Cancer 2015, 112:495-503 *equal contribution

Andree M, Seeger JM, Schüll S, Coutelle O, Wagner-Stippich D, Wiegmann K, Wunderlich C, Brinkmann K, Broxtermann PN, Witt A., Fritsch M, Martinelli P, Bielig H, Lamkemeyer T, Rugarli EI, Kaufmann T, Sterner-Koch A, Wunderlich, FT, Villunger A, Martins LM, Krönke M, Kufer T, Utermöhlen O, Kashkar H.
BID-mediated release of mitochondrial SMAC dampens XIAP-mediated immunity against Shigella. EMBO J. 2014, 33:2171-2187

Coutelle O, Hornig-Do HT, Witt A, Andree M, Schiffmann LM, Liwschitz M, Seeger JM, Piekarek M, Brinkmann K, Hallek M, Krönke M, Trifunovic A, Eming SA, Wiesner RJ, Hacker UT, Kashkar H.
Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing EMBO Mol. Med. 2014, 6:624-639

Brinkmann K, Zigrino P, Witt A, Schell M, Ackermann L, Broxtermann PN, Schüll S, Andree M, Coutelle O, Yazdanpanah B, Seeger JM, Klubertz D, Drebber U, Hacker UT, Krönke M, Mauch C, Hoppe T, Kashkar H.
Ubiquitin C-Terminal Hydrolase-L1 Potentiates Cancer Chemosensitivity by Stabilizing NOXA. Cell Rep. 2013, 3(3):881-91.

https://pubmed.ncbi.nlm.nih.gov/?term=kashkar+h&sort=date&size=20