Cellular FLICE-like Inhibitory Protein (c-FLIP) and PS1-associated Protein (PSAP) Mediate Presenilin 1-induced γ-Secretase-dependent and -independent Apoptosis, Respectively

Abstract

Background: The PS1-induced apoptosis mechanism is not fully understood. Results: PS1-induced apoptosis depends on PSAP-Bax complex formation and ␥-catalyzed turnover of c-FLIP. Conclusion: PS1 induces apoptosis through the ␥-secretase-dependent PS1-c-FLIP-caspase-8-Bid cascade and ␥-secretaseindependent PS1-PSAP cascade, which converge on Bax to activate the mitochondrial apoptotic pathway. PS2 induced apoptosis through a different pathway. Significance: This study provides new insight into the mechanism of PS1-induced apoptosis.

Nicastrin is required for amyloid precursor protein (APP) but not Notch processing, while anterior pharynx‐defective 1 is dispensable for processing of both APP and Notch

“…These results indicate that c-secretase inhibitor and proteasome inhibitor have an additive effect on the accumulation of unprocessed CTFa through different mechanisms. Furthermore, it was noted that in addition to regular PS1C produced by normal endoproteolytic processing of PS1, a short C-terminal fragment of PS1, CaspPS1C, which was produced by caspase activity (Zeng et al 2015), was detected in cells treated with MG132 (lanes 4, 7, and 9), and the formation of CaspPS1C was completely inhibited by the addition of pan caspase inhibitor Z-VAD (lanes 6, 8, and 10).…”

Soluble epoxide hydrolase promotes astrocyte survival in retinopathy of prematurity

“…In the retina, sEH is expressed in Müller glial cells as well as in astrocytes (15), but until now, physiological angiogenesis and retinopathy have only been linked with the paracrine effects of sEH tase-independent actions of PS-1 are reportedly mediated by its interaction with PSAP (28), which localizes to the mitochondrial membrane and induces apoptosis in a Bax/Bak-independent but caspase 3-dependent manner (28,29). This link fits well with the observed hyperoxia-induced dissociation of PS-1/PSAP complex and the translocation of PSAP to the inner mitochondrial membrane and caspase 3 activation that were prevented by 19,20-DHDP.…”

“…This unique behavior of 19,20-DHDP seems to be conserved in astrocyte mitochondrial membranes, and although it is not possible to definitively state that 19,20-DHDP can be generated within or proximal to astrocyte mitochondria, it should be noted that sEH is localized to mitochondria in the liver (43,44). The best-characterized cholesterol-linked protein targeted by 19,20-DHDP is PS-1, which was of particular interest, as it has also been attributed to γ-secretase-dependent and -independent proapoptotic effects in mitochondria (27,28). In addition, alterations in membrane cholesterol have also been linked with mitochondrial damage and death (26).…”

“…19,20-DHDP, but not 19,20-EDP, decreased cholesterol levels in the mitochondrial membrane and partially prevented the reduction in membrane potential triggered by cholesterol. The cholesterol-interacting protein, PS-1, was previously characterized as a target of 19,20-DHDP (15,25) and was of interest, as it has also been attributed to γ-secretase-dependent and -independent proapoptotic effects in mitochondria (27,28). Given the lack of effect of DAPT on astrocyte loss in the mouse model, work focused on γ-secretase-independent actions of PS-1, which are mainly mediated by its interaction with the PS-1-associated protein (PSAP; also known as mitochondrial carrier homolog 1) (28).…”

“…The cholesterol-interacting protein, PS-1, was previously characterized as a target of 19,20-DHDP (15,25) and was of interest, as it has also been attributed to γ-secretase-dependent and -independent proapoptotic effects in mitochondria (27,28). Given the lack of effect of DAPT on astrocyte loss in the mouse model, work focused on γ-secretase-independent actions of PS-1, which are mainly mediated by its interaction with the PS-1-associated protein (PSAP; also known as mitochondrial carrier homolog 1) (28). Under normoxic conditions, PS-1 and PSAP were colocalized in the same hydrophilic fractions (sucrose gradient) of the mitochondrial membrane (fractions 7-8) (Supplemental Figure 2, A and B).…”