Autophagic degradation of active caspase-8

Abstract

Apoptotic defects endow tumor cells with survival advantages. Such defects allow the cellular stress response to take the path of cytoprotective autophagy, which either precedes or effectively blocks an apoptotic cascade. Inhibition of the cytoprotective autophagic response shifts the cells toward apoptosis, by interfering with an underlying molecular mechanism of cytoprotection. The current study has identified such a mechanism that is centered on the regulation of caspase-8 activity. The study took advantage of Bax(-/-) Hct116 cells that are TRAIL-resistant despite significant DISC processing of caspase-8, and of the availability of a caspase-8-specific antibody that exclusively detects the caspase-8 large subunit or its processed precursor. Utilizing these biological tools, we investigated the expression pattern and subcellular localization of active caspase-8 in TRAIL-mediated autophagy and in the autophagy-to-apoptosis shift upon autophagy inhibition. Our results suggest that the TRAIL-mediated autophagic response counter-balances the TRAIL-mediated apoptotic response by the continuous sequestration of the large caspase-8 subunit in autophagosomes and its subsequent elimination in lysosomes. The current findings are the first to provide evidence for regulation of caspase activity by autophagy and thus broaden the molecular basis for the observed polarization between autophagy and apoptosis.

Apolipoprotein L6, Induced in Atherosclerotic Lesions, Promotes Apoptosis and Blocks Beclin 1-dependent Autophagy in Atherosclerotic Cells

“…autophagy can be used to degrade active caspase 8 and therefore blocking apoptosis (55). Our findings demonstrate that ApoL6 is one, if not the major, of the immediate regulators that controls levels and function of Beclin 1, Bcl-X L , and caspase 8 in apoptosis and autophagy because ApoL6 binds Bcl-X L , induces Beclin 1 degradation and subsequent autophagy inhibition.…”

Apoptosis promotes early tumorigenesis

“…Autophagy is a tumorsuppression mechanism, yet it enables tumor-cell survival in settings of enhanced stress (Kondo et al, 2005;Mathew et al, 2007;White and DiPaola, 2009). Moreover, autophagy can degrade active caspase-8 within tumor cells (Hou et al, 2010). Thus, one possible explanation for the findings would be the presence of a regulatory protein (for example, Flice inhibitory protein), which could be recruited to CD95 and regulate activation of JNK and autophagy that represses the potential pro-apoptotic function of CD95 and thereby promote tumor initiation.…”

TRAIL Induces Apoptosis and Autophagy

“…Inhibition of autophagy by the knockdown of "eclin 1, UVR"G, Vps34, or "tg7 allows for the induction of signiicant apoptosis in response to TR"IL [69]. The following work from this laboratory demonstrates that TR"IL-mediated autophagic response counterbalances the TR"IL-mediated apoptotic response by the continuous sequestration of the large caspase-8 subunit in autophagosomes and its subsequent elimination in lysosome [66]. Inhibition of autophagy induces caspase-8 activity these indings provide evidence for regulation of caspase activity by autophagy.…”