engleski

FAS-ASSOCIATED DEATH DOMAIN (FADD) IS NEGATIVE REGULATOR OF PROGRAMMED NECROSIS AND AUTOPHAGY TRIGGERED BY NARROWBAND ULTRAVIOLET B IRRADIATION

Programmed cell death (PCD) is a fundamental biological process, serving many important functions in animal development and homeostasis, and the pathogenesis of many diseases is attributed to its malfunctioning. Apoptosis was until recently the only process known to cause cell death in programmed manner. Recently, the term necroptosis has been used to designate one particular type of programmed necrosis that depends on the serine/threonine kinase activity of RIP1. Indeed, RIP1 represents the molecular target of a new class of cytoprotective agents, the necrostatins. Hiperautophagy has been suggested to cause necroptosis as well. FADD protein is critical adaptor protein for death receptor-mediated apoptosis. In addition, FADD is also implicated in non-apoptotic functions through interactions with partner-proteins. Based on the presumption that FADD protein intermediates apoptotic, as well as necroptotic and autophagic signals after exposure to NB-UVB irradiation, we tested its role of death adaptor using FADD knockout mouse embryonic fibroblasts and specific inhibitors, Necrostatin-1 and pan-caspase inhibitor Z-VAD-FMK. The results show that wild type mouse embryonic fibroblast die by triggering apoptotic death signals through mitochondrial control, but independently of p53. FADD knockout mouse embryonic fibroblasts die by programmed necrosis and autophagy, by activating caspase-3 and -9. Their necrotic programme does not involve p53 nor Bax and Bcl-2. The results show that protein FADD as well as RIP1 are essential for triggering apoptotic cell death after NB-UVB irradiation. FADD protein acts as negative regulator of necroptosis followed by autophagy.

FADD; necroptosis; autophagy

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