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Role for X-linked Inhibitor of apoptosis protein upstream of mitochondrial permeabilization
Thomas W Owens1, Fiona M Foster, Anthony Valentijn
1Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
Abstract:
Apoptosis is controlled by a signaling equilibrium between prosurvival and proapoptotic pathways, such that unwanted apoptosis is avoided, but when required it occurs rapidly and efficiently. Many apoptosis regulators display dual roles, depending upon whether a cell has received an apoptotic stimulus or not. Here, we identify a novel and unexpected function for X-linked inhibitor of apoptosis (XIAP) that occurs when apoptosis is triggered under physiological conditions. We show that in response to loss of survival signals provided by cell adhesion, endogenous XIAP translocates from the cytosol into a mitochondrial 400-kDa complex and that this occurs very early in the apoptosis process. Membrane-associated XIAP induces mitochondrial outer membrane permeabilization leading to cytochrome c and Smac release, which is dependent on Bax and Bak. Thus, although XIAP suppresses apoptosis in healthy cells, our data indicate that XIAP may contribute to it in response to a proapoptotic signal such as loss of extracellular matrix-dependent survival signaling. We suggest that, as with Bcl-2 family proteins, more diverse functions for XIAP exist than previously identified. Moreover, switching the function of proteins from anti- to proapoptotic forms may be a common theme in the efficient execution of cell death.
Insights
X-linked inhibitor of apoptosis (XIAP) normally prevents cell death but can promote apoptosis when cells lose survival signals. This protein shifts from the cytosol to mitochondria, initiating cell death pathways under physiological conditions.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Apoptosis is a tightly regulated process involving a balance between pro-survival and pro-apoptotic signals.
- Many proteins involved in apoptosis have context-dependent roles, acting differently in healthy versus stressed cells.
Purpose of the Study:
- To investigate the function of X-linked inhibitor of apoptosis (XIAP) in apoptosis under physiological conditions.
- To identify novel roles for XIAP beyond its known anti-apoptotic function.
Main Methods:
- Studied XIAP localization and function in response to loss of survival signals (e.g., cell adhesion).
- Investigated XIAP's translocation to mitochondrial complexes and its role in mitochondrial outer membrane permeabilization.
- Assessed the involvement of Bax and Bak in XIAP-mediated apoptosis.
Main Results:
- Endogenous XIAP translocates from the cytosol to a mitochondrial complex early in apoptosis upon loss of survival signals.
- Mitochondrial XIAP induces outer membrane permeabilization, leading to cytochrome c and Smac release.
- This pro-apoptotic function of XIAP is dependent on Bax and Bak.
Conclusions:
- XIAP exhibits a dual role, suppressing apoptosis in healthy cells but promoting it when survival signals are lost.
- XIAP's function can switch from anti-apoptotic to pro-apoptotic, contributing to efficient cell death execution.
- This highlights diverse functions for XIAP and suggests functional switching is a common mechanism in apoptosis regulation.
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