Introduction

Cells undergo cell death in many forms and due to different insults. Programmed cell death (PCD) is crucial for correct development of the organism and the clearance of harmful cells like tumor cells or autoreactive immune cells. PCD is initiated by the activation of cell death receptors and in most cases it is associated with the activation of the cysteine proteases caspases, which lead to apoptotic cell death; cells shrink, chromatin clumps and forms a large, sharply demacrated, crescent-shaped or round masses, the nucleus condenses, apoptotic bodies are formed and eventually dead cells are engulfed by a neighboring cell or cleared by phagocytosis (Kerr et al. 1972). Other insults can trigger this ordered disposal of a cell, such as radiation leading to DNA damage, via p53 which in turn activates the apoptotic pathway (Xiang et al. 1996). The classical caspase-dependent cell death pathway has been studied in great detail not only in mammalian cells, but also in model organisms C. elegans and Drosophila (Hengartner 2000; Danial and Korsmeyer 2004; Hay and Guo 2006; Lettre and Hengartner 2006).

The view of apoptosis as the only form of PCD, entirely dependent on caspases, is now challenged by several findings in both C. elegans and Drosophila. Several paradigms of cell death have been shown to be executed independently of caspases: autophagy, necrosis, and even apoptosis (Broker et al. 2005; Kroemer and Martin 2005; Stefanis 2005). Different cell organelles have been implicated in contributing to cell death in a caspase-independent manner with the mitochondrion playing the central role by releasing death executors from the intermembrane space to the cyto-sol, triggering the breakdown of the cell (Lorenzo and Susin 2004; Kim et al. 2006). Here, we review caspase-independent cell death mechanisms and relevant genes in the nematode and the fruit fly (Table 2.1). We discuss the roles of autophagy and necrosis and possible interplay between caspase-dependent and -independent

M. Rieckher and N. Tavernarakis (*)

Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Vassilika Vouton, PO Box 1385, Heraklion, 71110, Crete, Greece e-mail: [email protected]

D.G. Fujikawa (ed.), Acute Neuronal Injury: The Role of Excitotoxic Programmed Cell Death Mechanisms, DOI 10.1007/978-0-387-73226-8_2, © Springer Science+Business Media, LLC 2010

Table 2.1 Proteins implicated in caspase-independent cell death mechanisms in mammals and their homologs in C. elegans and Drosophila (Proteins involved in autophagic cell death are discussed in Baehrecke 2003; Samara and Tavernarakis 2008) Mitotic catastrophy Mammals

Omi/HtrA2

WWOX

Autophagy

Induction of autophagy

Atgl UNC-51 Atgl Ser/Thr protein kinase Kamada et al. (2000)

TOR1/TOR2 LET-363 Tor Rapamycin-sensitive Ser/Thr protein Scott et al. (2004)

kinase

Autophagosome nucleation

Atg6 BEC-1 Atg6 Component of class III PI3-kinase Furuya et al. (2005)

complex

VPS34 VPS-34 Vps34 Class III PI3-kinase Furuya et al. (2005)

Autophagosome maturation

Atg3 Y55F3AM.4 Autl E2-like enzyme

Atg4 Y87G2A.3 Atg4 Cys protease

Atg5 ATGR-5 Atg5 Scott et al. (2004)

Atg7 ATGR-7 Atg7 El-like enzyme Juhasz et al. (2007a)

Atg8 LGG-1 - Ubiquitin-hke protein conjugated to PE Juhasz et al. (2007b)

AtglO D2085.2 - E2-like enzyme

Atgl2 LGG-3 Atgl2 Ubiquitin-hke protein

Atgl 6 K06A1.5

C. elegans

WAH-1

CPS-6

  1. 10. C13C4.5. CEF09A5
  2. melanogaster fAIF

CG8862

dOmi spin

DmWWOX

Protein function (FAD)-binding oxidoreductase Sequence-unspecific DNase Serine protease

Oxido-reductase (FAD)-binding oxidoreductase (FAD)-binding oxidoreductase

Refs

Wang et al. (2002) Parrish et al. (2001) Challa et al. (2007) Nakano et al. (2001)

O ' Keefe et al. (2005) Wu et al. (2002) Ohiro et al. (2002)

  1. elegans
  2. melanogaster Protein function

Refs

AUT2/APG4 AUT7/APG8/CVT5

Autophagic protein retrival

Atg2

Atg9

Atgl8

Necrosis

Mammals

Adenylyl cyclase

Calnexin

Calreticulin

Mucolipin-1

Ryanodine receptor

ATGR-9 ATGR-18

C. elegans

ACY-1

ASP-3

ASP-4

CAD-1

CLP-1

CNX-1

CRT-1

CUP-5

DAF-2

DAT-1

ITR-1

PQE-1

SGS-1

SPE-5

TRA-3

UNC-68

UNC-32

VHA-2

VHA-10

VHA-12

CGI 694 Atg8a

Atg8b

Atg2 Atg9 Atgl8

Cysteine-type endopeptidase Microtubule binding; cytoskeleton biogenesis Microtubule binding; cytoskeleton biogenesis

Integral membrane protein

Protein function Adenylyl cyclase Aspartyl protease Aspartyl protease

Calcium-activated cysteine protease ER Ca2+ binding chaperone ER Ca2+ binding-storing protein

Receptor of insulin-like ligands Dopamine transporter Inositol triphosphate receptor ion channel Q/P-rich protein Adenylyl cyclase Vacuolar H+-ATPase B subunit Calcium-activated cysteine protease ER Ca2+ release channel Vacuolar H+-ATPase a subunit Vacuolar H+-ATPase c subunit Vacuolar H+-ATPase G subunit Vacuolar H+-ATPase B subunit

Thumm and Kadowaki (2001) Simonsen et al. (2008)

Samara and Tavernarakis (2008) Samara and Tavernarakis (2008) Samara and Tavernarakis (2008)

Refs

Berger et al. (1998) Syntichaki et al. (2002) Syntichaki et al. (2002) Artal-Sanz et al. (2006) Syntichaki et al. (2002) Xu et al. (2001) Xu et al. (2001) Artal-Sanz et al. (2006) Scott et al. (2002) Nass et al. (2002) Xu et al. (2001) Faber et al. (2002) Korswagen et al. (1998) Syntichaki et al. (2005) Syntichaki et al. (2002) Xu et al. (2001) Syntichaki et al. (2005) Syntichaki et al. (2005) Syntichaki et al. (2005) Syntichaki et al. (2005)_

pathways leading to cell death, as well as their implication in disorders like neurodegenerative diseases. Recent research has also provided evidence for additional novel forms of cell death in C. elegans and Drosophila, indicating that current cell death classification may need to be revisited in the future.

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