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AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics

AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics Cell death has been initially divided into apoptosis, in which the cell plays an active role, and necrosis, which is considered a passive cell death program. Intense research performed in the last decades has concluded that “programmed” cell death (PCD) is a more complex physiological process than initially thought. Indeed, although in most cases the PCD process is achieved via a family of Cys proteases known as caspases, an important number of regulated PCD pathways do not involve this family of proteases. As a consequence, active forms of PCD are initially referred to as caspase‐dependent and caspase‐independent. More recent data has revealed that there are also active caspase‐independent necrotic pathways defined as necroptosis (programmed necrosis). The existence of necroptotic forms of death was corroborated by the discovery of key executioners such as the kinase RIP1 or the mitochondrial protein apoptosis‐inducing factor (AIF). AIF is a Janus protein with a redox activity in the mitochondria and a pro‐apoptotic function in the nucleus. We have recently described a particular form of AIF‐mediated caspase‐independent necroptosis that also implicates other molecules such as PARP‐1, calpains, Bax, Bcl‐2, histone H2AX, and cyclophilin A. From a therapeutic point of view, the unraveling of this new form of PCD poses a question: is it possible to modulate this necroptotic pathway independently of the classical apoptotic paths? Because the answer is yes, a wider understanding of AIF‐mediated necroptosis could theoretically pave the way for the development of new drugs that modulate PCD. To this end, we present here an overview of the current knowledge of AIF and AIF‐mediated necroptosis. We also summarize the state of the art in some of the most interesting therapeutic strategies that could target AIF or the AIF‐mediated necroptotic pathway. © 2011 IUBMB IUBMB Life, 63(4): 221–232, 2011 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png IUBMB Life Wiley

AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics

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References (109)

Publisher
Wiley Subscription Services, Inc., A Wiley Company
Copyright
Copyright © 2011 Wiley Periodicals, Inc.
ISSN
1521-6543
eISSN
1521-6551
DOI
10.1002/iub.432
pmid
21438113
Publisher site
See Article on Publisher Site

Abstract

Cell death has been initially divided into apoptosis, in which the cell plays an active role, and necrosis, which is considered a passive cell death program. Intense research performed in the last decades has concluded that “programmed” cell death (PCD) is a more complex physiological process than initially thought. Indeed, although in most cases the PCD process is achieved via a family of Cys proteases known as caspases, an important number of regulated PCD pathways do not involve this family of proteases. As a consequence, active forms of PCD are initially referred to as caspase‐dependent and caspase‐independent. More recent data has revealed that there are also active caspase‐independent necrotic pathways defined as necroptosis (programmed necrosis). The existence of necroptotic forms of death was corroborated by the discovery of key executioners such as the kinase RIP1 or the mitochondrial protein apoptosis‐inducing factor (AIF). AIF is a Janus protein with a redox activity in the mitochondria and a pro‐apoptotic function in the nucleus. We have recently described a particular form of AIF‐mediated caspase‐independent necroptosis that also implicates other molecules such as PARP‐1, calpains, Bax, Bcl‐2, histone H2AX, and cyclophilin A. From a therapeutic point of view, the unraveling of this new form of PCD poses a question: is it possible to modulate this necroptotic pathway independently of the classical apoptotic paths? Because the answer is yes, a wider understanding of AIF‐mediated necroptosis could theoretically pave the way for the development of new drugs that modulate PCD. To this end, we present here an overview of the current knowledge of AIF and AIF‐mediated necroptosis. We also summarize the state of the art in some of the most interesting therapeutic strategies that could target AIF or the AIF‐mediated necroptotic pathway. © 2011 IUBMB IUBMB Life, 63(4): 221–232, 2011

Journal

IUBMB Life – Wiley

Published: Apr 1, 2011

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