Hsp72 Inhibits Fas-mediated Apoptosis Upstream of the Mitochondria in Type II Cells

Nicholas J Clemons,Katherine Buzzard,Rohan Steel,Robin L Anderson

doi:10.1074/jbc.m414165200

Nicholas J Clemons, Katherine Buzzard + Show 2 more

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https://doi.org/10.1074/jbc.m414165200

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Abstract

Heat shock protein 72 (Hsp72) inhibits apoptosis induced by some stresses that trigger the intrinsic apoptosis pathway. However, with the exception of TNFalpha-induced apoptosis, a role for Hsp72 in modulating the extrinsic pathway of apoptosis has not been clearly established. In this study, it was demonstrated that Hsp72 could inhibit Fas-mediated apoptosis of type II CCRF-CEM cells, but not type I SW480 or CH1 cells. Similar results were obtained when Fas ligand or an agonistic Fas antibody initiated the Fas apoptosis pathway. In CCRF-CEM cells, Hsp72 inhibited mitochondrial membrane depolarization and cytochrome c release but did not alter surface Fas expression or processing of caspase-8 and Bid, indicating that Hsp72 acts upstream of the mitochondria to inhibit Fas-mediated apoptosis. Thus, the ability of Hsp72 to inhibit Fas-mediated apoptosis is limited to type II cells where involvement of the intrinsic pathway is required for efficient effector caspase activation.

Highlights

Apoptosis is a tightly regulated, genetically controlled event crucial to normal development and tissue homeostasis [1, 2]
Apoptosis was induced in CCRF-CEM cells in a dose-dependent manner, but was reduced by ϳ50% at all doses in the Heat shock protein 72 (Hsp72)-expressing clones compared with parental cells or vector control cells
In this study we demonstrate that Hsp72 is capable of inhibiting apoptosis induced by Fas signaling, but only in Type II cells where recruitment of the intrinsic pathway is required for the successful initiation of apoptosis

Summary

Introduction

Apoptosis is a tightly regulated, genetically controlled event crucial to normal development and tissue homeostasis [1, 2]. Apoptosis can be divided into two distinct but interconnecting pathways: the extrinsic pathway that is activated upon ligation of death receptors of the TNF1 receptor superfamily and the intrinsic pathway that is initiated by cellular stresses that activate pro-apoptotic members of the Bcl-2 family to target the mitochondria. Central to both pathways are the caspases, which cleave a specific set of target substrates leading to the classic hallmarks of apoptosis [5]. Hsp could not inhibit Fas-induced apoptosis in the type I cells indicating that Hsp acts only in the intrinsic pathway

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