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Updated: Jun 5, 2026

A Fluorescence-based Assay of Phospholipid Scramblase Activity

A Fluorescence-based Assay of Phospholipid Scramblase Activity

Published on: September 20, 2016

c-FLIP: A pseudoprotease with emerging metal-binding activity.

Rhea Sarah DSouza^1,2, Yusuke Nakasone³, Naoyuki Iwabe⁴

¹Graduate School of Biostudies, Kyoto University, Kyoto, Japan.

The FEBS Journal

|June 4, 2026

Summary

This summary is machine-generated.

Cellular FLICE-like inhibitory protein (c-FLIP) evolved from an active enzyme to a pseudoenzyme, gaining iron-binding and oxidative stress protection functions beyond its known anti-apoptotic role.

Keywords:

Fenton reaction LYR motif ferrous ion pseudoenzyme redox homeostasis

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Area of Science:

Biochemistry
Evolutionary Biology
Cellular Biology

Background:

Proteins can evolve novel functions by transitioning from active enzymes to inactive pseudoenzymes.
Cellular FLICE-like inhibitory protein (c-FLIP) is a pseudoenzyme that diverged from caspase-8 (Casp8), acquiring anti-apoptotic functions.
Structural and phylogenetic analyses suggested a potential iron-binding role for c-FLIP's pseudoprotease domain (CASc*).

Purpose of the Study:

To investigate if c-FLIP acquired iron-binding capabilities beyond its canonical apoptotic function.
To explore the role of the conserved LYR triad in c-FLIP's pseudoprotease domain.
To understand the implications of c-FLIP's iron-binding function in cellular oxidative stress and evolution.

Main Methods:

Biochemical assays to test Fe2+ binding and inhibition of hydroxyl radical generation.
Cytological analyses in E. coli and cultured cells to assess protection against oxidative stress.
Phylogenetic and structural analyses of the c-FLIP protein family.
Identification of a secondary promoter regulating CASc-only isoform expression.

Main Results:

CASc* confirmed to bind Fe2+ ions and inhibit Fenton reaction-mediated hydroxyl radical production.
Expression of CASc* conferred protection against oxidative stress induced by Fe2+ and H2O2 in bacterial and cultured cells.
A novel secondary promoter in CFLAR intron 5 was found to drive CASc-only isoform expression in specific fetal cell lines.
c-FLIP exhibits a dual role in iron-dependent redox regulation and apoptosis signaling.

Conclusions:

c-FLIP has evolved a novel iron-binding function, enabling it to regulate redox balance and protect cells from oxidative stress.
This pseudoenzyme adaptation highlights an evolutionary strategy for acquiring new cellular roles.
The findings reveal c-FLIP's complex involvement in both apoptosis and iron-mediated oxidative stress defense.