Caspase-3 feeds back on caspase-8, Bid and XIAP in type I Fas signaling in primary mouse hepatocytes
2012 (English)In: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 17, no 5, 503-515 p.Article in journal (Refereed) Published
The TNF-R1 like receptor Fas is highly expressed on the plasma membrane of hepatocytes and plays an essential role in liver homeostasis. We recently showed that in collagen-cultured primary mouse hepatocytes, Fas stimulation triggers apoptosis via the so-called type I extrinsic signaling pathway. Central to this pathway is the direct caspase-8-mediated cleavage and activation of caspase-3 as compared to the type II pathway which first requires caspase-8-mediated Bid cleavage to trigger mitochondrial cytochrome c release for caspase-3 activation. Mathematical modeling can be used to understand complex signaling systems such as crosstalks and feedback or feedforward loops. A previously published model predicted a positive feedback loop between active caspases-3 and -8 in both type I and type II FasL signaling in lymphocytes and Hela cells, respectively. Here we experimentally tested this hypothesis in our hepatocytic type I Fas signaling pathway by using wild-type and XIAP-deficient primary hepatocytes and two recently characterized, selective caspase-3/-7 inhibitors (AB06 and AB13). Caspase-3/-7 activity assays and quantitative western blotting confirmed that fully processed, active p17 caspase-3 feeds back on caspase-8 by cleaving its partially processed p43 form into the fully processed p18 species. Our data do not discriminate if p18 positively or negatively influences FasL-induced apoptosis or is responsible for non-apoptotic aspects of FasL signaling. However, we found that caspase-3 also feeds back on Bid and degrades its own inhibitor XIAP, both events that may enhance caspase-3 activity and apoptosis. Thus, potent, selective caspase-3 inhibitors are useful tools to understand complex signaling circuitries in apoptosis.
Place, publisher, year, edition, pages
Springer Verlag (Germany) , 2012. Vol. 17, no 5, 503-515 p.
Type I apoptosis, Caspase-3, Caspase-8, Caspase inhibitor, Feedback loop, Bid, XIAP
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-77089DOI: 10.1007/s10495-011-0691-0ISI: 000302569700007OAI: oai:DiVA.org:liu-77089DiVA: diva2:524971
Funding Agencies|Virtual Liver Network||German Federal Ministry of Education and Research||National Institutes of Health (NIH)|R01 EB005011|Excellence Initiative of the German Federal and State Governments|GSC-4|2012-05-042012-05-042012-05-04