ASC-mediated NF-κB Activation Leading to Interleukin-8 Production Requires Caspase-8 and Is Inhibited by CLARP

Mechanism of ASC-mediated apoptosis: Bid-dependent apoptosis in type II cells

“…Consistent with this report, BAXÀ/À HCT116 cells, Figure 4b). However, when we coexpressed ASC and Bax in COS7 cells and examined their colocalization with mitochondria using Mitotracker, ASC formed aggregates called 'specks' as described previously (Hasegawa et al, 2005) and did not colocalize with the mitochondria, whereas Bax showed clear localization at the mitochondria (Figure 4c, upper panels). In contrast, ASC and caspase-8 coexpressed in COS7 cells colocalized at the specks (Figure 4c, lower panels).…”

“…MDP stimulation induced the interaction of C12N2 and ASC, oligomerization of ASC and caspase-8-dependent NF-kB activation, leading to IL-8 production in these cell lines (Hasegawa et al, 2005). Furthermore, upon MDP stimulation, some MAIL8 cell lines showed clear apoptotic changes, such as plasma membrane blebbing, cell shrinkage (Figure 1a), phosphatidyl-serine externalization (Figure 1b), nuclear condensation and fragmentation, and the degradation of chromosomal DNA to nucleosome-sized units (Supplementary Figure 1).…”

“…(While we were revising this paper, a physiological stimulus for CARD12 was reported to be bacterial flagellin.) To overcome this problem, we recently established an experimental system in which muramyl dipeptide (MDP) activates ASC-mediated signal-transduction pathways through a chimeric protein (C12N2) consisting of the CARD (ASC-interacting domain) from CARD12 and the nucleotide-binding oligomerization domain and leucine-rich repeats (MDPbinding region) from Nod2, another Apaf-1-like protein (Hasegawa et al, 2005). Here, using this system, we investigated the molecular mechanisms of ASCmediated apoptosis in several cell lines.…”

Dual role of TMS1/ASC in death receptor signaling

“…Thus, the possibility exists that TMS1 drives caspase-8 cleavage by engaging a cytoplasmic pool of caspase-8. Indeed, there is evidence that TMS1 interacts directly with caspase-8, and colocalizes with caspase-8 in the cytoplasm in co-transfection experiments Hasegawa et al, 2005). Consistent with this idea, Masumoto et al (2003) showed that TMS1-induced apoptosis cannot be blocked by a dominant-negative FADD mutant consisting only of the death domains.…”

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…These results suggest that caspase-8 plays a significant role in the regulation of NF-jB in the innate immune response towards bacterial infection; however, the functional role in the regulation of the infectious bacteria is not clear. Human caspase-8 also contributes to NF-jB activation, leading to IL-8 production in response to muramyl dipeptide stimulation (Hasegawa et al 2005). Individuals containing a mutation in the caspase-8 gene show immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections (Chun et al 2002).…”