The short prodomain influences caspase-3 activation in HeLa cells

Meergans, Thomas; Hildebrandt, Ann-Kristin; Horák, Daniel; Haenisch, Christina; WENDEL, Albrecht

doi:10.1042/bj3490135

Cited by 25 publications

(3 citation statements)

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“…Previous studies demonstrated in a cell-free system that there are two cleavage events to form the p17 and p12 subunits 10 . While one study concluded that removal of the prodomain resulted in a constitutively active caspase-3 15 , others have demonstrated that the prodomain does not influence apoptotic activity 22 . These studies expressed caspase-3 transiently.…”

Section: Discussionmentioning

confidence: 99%

“…The apoptotic activity of caspase-3 is well characterized, but the regulation of this process is not fully understood. Previous studies demonstrated that the complete removal of the prodomain enhances apoptotic activity 15 . However, it is unknown whether this induction results in complete activation of caspase-3 or lowers the activation threshold.…”

Section: Introductionmentioning

confidence: 99%

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The prodomain of caspase-3 regulates its own removal and caspase activation

Ponder

Boise

2019

Cell Death Discovery

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Caspase-3 is a cysteine–aspartic acid protease that cleaves cellular targets and executes cell death. Our current understanding is caspase-3 is activated by the cleavage of the interdomain linker and then subsequent cleavage of the N-terminal prodomain. However, previous reports have suggested that removal of the prodomain can result in the constitutive activation of caspase-3, although other studies have not observed this. To address this question in a more physiological setting, we developed an inducible doxycycline system to express a mutant form of caspase-3 that lacks the prodomain (∆28). We found that the removal of the prodomain renders the cells more susceptible to death signals, but the caspase is not constitutively active. To elucidate the regions of the prodomain that regulate activity, we created deletion constructs that remove 10 and 19 N-terminal amino acids. Surprisingly, removal of the first 10 amino acids renders caspase-3 inactive. Following serum withdrawal, the interdomain linker is cleaved, however, the remaining prodomain is not removed. Therefore, there is a specific amino acid or stretch of amino acids within the first 10 that are important for prodomain removal and caspase-3 function. We created different point mutations within the prodomain and found amino acid D9 is vital for caspase-3 function. We hypothesize that an initial cleavage event at D9 is required to allow cleavage at D28 that causes the complete removal of the prodomain allowing for full caspase activation. Together these findings demonstrate a previously unknown role of the prodomain in caspase activation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The prodomain of caspase-3 regulates its own removal and caspase activation

Ponder

Boise

2019

Cell Death Discovery

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“…The significance of short prodomains, found on caspases 3, 6, 7, and 14, is unclear. It is possible that they serve as intermolecular recognition sites, as subcellular localization signals, or as regulators of caspase activity (14–16). Regardless of the type, however, the prodomain is removed during proteolytic processing, and the remaining molecule is further cleaved into large (p20) and small (p10) subunits.…”

Section: The Road To Destructionmentioning

confidence: 99%

Caspases and T lymphocytes: a flip of the coin?

Lakhani¹

2003

Immunological Reviews

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In this review, we consider the role caspases play in cell death downstream of death receptors and cell intrinsic death mechanisms. In particular, we focus on these mechanisms in antigen-induced cell death, a mechanism which regulates the number of surviving T cells at the end of an immune response. The relative role of the apoptosome as an amplifier rather than an initiator of apoptosis is considered. Several factors that regulate the susceptibility to activation-induced cell death are considered. These factors emanate from the stimulation of the T-cell receptors and include multiple pathways. Recent work has shown that death receptor signaling can play an interesting role in cell proliferation in both humans and animals. These recent findings are discussed in the light of models of death receptor signaling.

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Caspases

Denault

Salvesen

2001

CP Protein Science

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Caspases are a family of cysteine proteases with a strict specificity for aspartate residues involved in inflammatory process and programmed cell death. This overview unit provides basic information on their structure, enzymatic activity, substrate specificity, activation,inhibition and their implication in pathologies. It is intended to be an overview for investigators that are unfamiliar with this family of enzymes but it is also applicable to scientists pursuing research in this field.

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The short prodomain influences caspase-3 activation in HeLa cells

Cited by 25 publications

References 0 publications

The prodomain of caspase-3 regulates its own removal and caspase activation

The prodomain of caspase-3 regulates its own removal and caspase activation

Caspases and T lymphocytes: a flip of the coin?

Caspases

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