Aufklärung der molekularen Mechanismen zur Caspase-2 Aktivierung
Akustik
Biochemie
Zusammenfassung der Projektergebnisse
Caspases are key enzymes that mediate apoptosis, an evolutionarily conserved form of programmed cell death. Depending on the chronology of activation the caspases are divided into initiator caspases and effector caspases. Caspase-2 is an evolutionarily conserved member of the caspase family with unique features and despite intensive investigations, relatively little is understood on the molecular mechanisms driving the activation of this caspase. We originally identified that pore forming toxins, a major class of bacterial virulence factors, induce apoptotic cell death in epithelial cells, fibroblasts and keratinocytes in a caspase-2-dependent manner. Along on these lines, we identified that Apoptosis Inhibitor 5 (API5/AAC11) as an endogenous inhibitor of caspase-2. Like many initiator caspases, caspase-2 is dimerized through its CARD (Caspase Recruitment Domain) for its activation and we discovered that API5 directly inhibits this process by directly binding to this domain. API5 did not bind to the CARD domains of caspase-1 and caspase-9. Depletion of API5 led to enhanced dimerization and activation of caspases-2 and thus sensitizing cells to PFT-mediated apoptosis. These results thus unveiled the first, endogenous inhibitor of caspase-2, the first cloned mammalian caspase.
Projektbezogene Publikationen (Auswahl)
- Attenuation of the ELAV1-like protein HuR sensitizes adenocarcinoma cells to the intrinsic apoptotic pathway by increasing the translation of caspase-2L. Cell Death Dis. 2014 Jul 10;5:e1321
Winkler C, Doller A, Imre G, Badawi A, Schmid T, Schulz S, Steinmeyer N, Pfeilschifter J, Rajalingam K, Eberhardt W
(Siehe online unter https://doi.org/10.1038/cddis.2014.279) - Apoptosis inhibitor 5 is an endogenous inhibitor of caspase-2. EMBO Rep. 2017 May;18(5):733-744
Imre G, Berthelet J, Heering J, Kehrloesser S, Melzer IM, Lee BI, Thiede B, Dötsch V, Rajalingam K
(Siehe online unter https://doi.org/10.15252/embr.201643744)
