IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms

Tenev, Tencho; Zachariou, Anna; Wilson, Roger H. L.; Ditzel, Mark; Meier, Pascal

doi:10.1038/ncb1204

Cited by 139 publications

(156 citation statements)

References 29 publications

Supporting

Mentioning

153

Contrasting

Order By: Relevance

“…16 Fourth, Diap1, which is essential for cellular survival, 2,3 can inhibit DrICE through direct physical interactions. 4,5,20,21 These observations imply, but do not prove, that drICE encodes an important component of the apoptotic machinery in Drosophila. Thus, to clarify the role of drICE for developmental apoptosis, analysis of mutations in the endogenous gene are necessary.…”

Section: Introductionmentioning

confidence: 84%

The effector caspases drICE and dcp-1 have partially overlapping functions in the apoptotic pathway in Drosophila

et al. 2006

View full text Add to dashboard Cite

Caspases are essential components of the apoptotic machinery in both vertebrates and invertebrates. Here, we report the isolation of a mutant allele of the Drosophila effector caspase drICE as a strong suppressor of hid-(head involution defective-) induced apoptosis. This mutant was used to determine the apoptotic role of drICE. Our data are consistent with an important function of drICE for developmental and irradiation-induced cell death. Epistatic analysis suggests that drICE acts genetically downstream of Drosophila inhibitor of apoptosis protein 1 (Diap1). However, although cell death is significantly reduced in drICE mutants in all assays, it is not completely blocked. A double-mutant analysis between drICE and death caspase-1 (dcp-1), another effector caspase, reveals that some cells (type I) strictly require drICE for apoptosis, whereas other cells (type II) require either drICE or dcp-1. Thus, these data demonstrate a barely appreciated complexity in the apoptotic pathway, and are consistent with current models about effector caspase regulation in both vertebrates and invertebrates.

show abstract

Section: Introductionmentioning

confidence: 84%

The effector caspases drICE and dcp-1 have partially overlapping functions in the apoptotic pathway in Drosophila

et al. 2006

View full text Add to dashboard Cite

show abstract

“…52 DIAP1 can also bind to processed effector caspases such as DrICE and DCP1 via conserved IAP-binding motifs (IBMs) in the neo-amino-termini of the large caspase subunits. 53 Although some groups report DIAP1 inhibits DrICE, 21 another group suggests that, like cIAP1 and cIAP2, DIAP1 may not inhibit the proteolytic activity of effector caspases even while bound to them. 53 …”

Section: Iapsmentioning

confidence: 99%

“…53 Although some groups report DIAP1 inhibits DrICE, 21 another group suggests that, like cIAP1 and cIAP2, DIAP1 may not inhibit the proteolytic activity of effector caspases even while bound to them. 53 …”

Section: Iapsmentioning

confidence: 99%

Caspase inhibitors: viral, cellular and chemical

2006

View full text Add to dashboard Cite

“…There are several possibilities. For example, because IAPs require effector caspases for inhibitory activity, 55,56 it may be possible that a wt/class C heterotetramer does not produce as much active DIAP1 compared with a wild-type tetramer. Specifically, the N terminus of DIAP1 is an intramolecular inhibitor of DIAP1, keeping DIAP1 in an auto-inhibited conformation, unable to bind and inhibit DrICE.…”

Section: Discussionmentioning

confidence: 99%

Genetic characterization of two gain-of-function alleles of the effector caspase DrICE in Drosophila

Lindblad

Garnett

et al. 2015

Cell Death Differ

View full text Add to dashboard Cite

Caspases are the executioners of apoptosis. Although much is known about their physiological roles and structures, detailed analyses of missense mutations of caspases are lacking. As mutations within caspases are identified in various human diseases, the study of caspase mutants will help to elucidate how caspases interact with other components of the apoptosis pathway and how they may contribute to disease. DrICE is the major effector caspase in Drosophila required for developmental and stressinduced cell death. Here, we report the isolation and characterization of six de novo drICE mutants, all of which carry point mutations affecting amino acids conserved among caspases in various species. These six mutants behave as recessive loss-offunction mutants in a homozygous condition. Surprisingly, however, two of the newly isolated drICE alleles are gain-of-function mutants in a heterozygous condition, although they are loss-of-function mutants homozygously. Interestingly, they only behave as gain-of-function mutants in the presence of an apoptotic signal. These two alleles carry missense mutations affecting conserved amino acids in close proximity to the catalytic cysteine residue. This is the first time that viable gain-of-function alleles of caspases are described in any intact organism and provides a significant exception to the expectation that mutations of conserved amino acids always abolish the pro-apoptotic activity of caspases. We discuss models about how these mutations cause the gain-offunction character of these alleles. Cell Death and Differentiation (2016) 23, 723-732; doi:10.1038/cdd.2015.144; published online 6 November 2015Apoptosis is a major form of programmed cell death. 1 The core apoptotic machinery is evolutionary conserved with caspases as the fundamental components. [1][2][3] Caspases are specific cysteine proteases that are produced as inactive zymogens composed of an N-terminal pro-domain, a large subunit region with the catalytic cysteine residue, and a small subunit region at the carboxyl end. 2,4 Depending on their structures and functions, caspases are grouped into initiator and effector caspases. 2,3 Initiator caspases possess long pro-domains, which facilitate the recruitment of initiator caspases into cell death signaling complexes for activation. 2,3,5 Effector caspases are activated by initiator caspase complexes through proteolytic processing, cleaving off the pro-domain and separating the large and small subunits. The active effector caspase is a tetramer composed of two large and two small subunits and contains two catalytic sites. 2,3 Activated effector caspases cleave many protein targets to trigger the physiological and morphological changes characteristic of apoptosis. In mammals, apoptotic initiator caspases are Caspase-8, -9, -2 and -10, and effector caspases involved in apoptosis are 3 Of the seven Drosophila caspases, only the initiator caspase Dronc (Caspase-9-like) and the effector caspases DrICE and Dcp-1 (Caspase-3-like) have been implicated in apoptosis in imagina...

show abstract

IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms

Cited by 139 publications

References 29 publications

The effector caspases drICE and dcp-1 have partially overlapping functions in the apoptotic pathway in Drosophila

The effector caspases drICE and dcp-1 have partially overlapping functions in the apoptotic pathway in Drosophila

Caspase inhibitors: viral, cellular and chemical

Genetic characterization of two gain-of-function alleles of the effector caspase DrICE in Drosophila

Contact Info

Product

Resources

About