Caspase‐3‐truncated type 1 inositol 1,4,5‐trisphosphate receptor enhances intracellular Ca<sup>2+</sup> leak and disturbs Ca<sup>2+</sup> signalling

Verbert, Leen; Lee, Bora; Kocks, Sarah L.; Assefa, Zerihun; Parys, Jan B.; Missiaen, Ludwig; Callewaert, Geert; Fissore, Rafael A.; Smedt, Humbert De; Bultynck, Geert

doi:10.1042/bc20070086

Cited by 48 publications

(48 citation statements)

References 52 publications

(59 reference statements)

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“…undergoes proteolysis in a manner consistent with previous studies in DT40 cells and several other cell types (22)(23)(24)(25). More importantly, our experiments suggest that during apoptosis, IP 3 R1 is cleaved into two overlapping N-terminal fragments encompassing the suppressor domain, the ligand-binding domain, and most of the coupling domain and a C-terminal fragment containing the channel domain and the cytosolic tail.…”

Section: Characterizing Ip 3 R1 Fragmentation Patterns During Apoptosis-supporting

confidence: 74%

“…7E. Previous studies showed that transient expression of the C-terminal 95-kDa-fragment resulted in a modest depletion of ER stores (22,27,30). However, examination of resting Ca 2ϩ levels and the content of intracellular Ca 2ϩ stores, as judged by the rate and magnitude of cyclopiazonic acid -induced Ca 2ϩ release, showed no significant difference between these cell lines, expressing channel-only fragments and IP 3 R1 cells or FIGURE 7.…”

Section: Characterizing Ip 3 R1 Fragmentation Patterns During Apoptosis-mentioning

confidence: 97%

“…For example, IP 3 R1 was shown to undergo caspase 3-dependent cleavage in various cell types, and this cleavage led to the formation of a C-terminal constitutively leaky channel termed a "channel-only domain" that mediates Ca 2ϩ release essential for complete execution of the apoptotic program (22,24,27). In contrast, it has been reported that IP 3 R1 is not cleaved in HEK293, HeLa, and Jurkat cells undergoing apoptosis in response to exposure to staurosporine, TNF␣, Trail, or UV irradiation (43).…”

Section: Discussionmentioning

confidence: 99%

“…However, no consensus exists as to whether particular IP 3 R isoforms are specifically required or, alternatively, whether individual IP 3 R isoforms can function in a redundant fashion (17)(18)(19)(20)(21). Several studies have shown that during apoptosis, IP 3 R1 is proteolytically cleaved in a caspase-dependent manner (22)(23)(24)(25). These studies further suggested that cleavage is crucial to mediating the dysregulated Ca 2ϩ signaling events (24).…”

mentioning

confidence: 99%

“…The emerging paradigm from these studies is that proteolytic cleavage occurs at the junction between the central modulatory domain and the channel domain. In this scenario, cleavage uncouples the N-terminal ligand-binding domain from the channel domain and, thus, terminates IP 3 -mediated Ca 2ϩ release (22,26). In addition, on the basis of the observation that transient expression of the C-terminal 95-kDa channel fragment resulted in the formation of constitutively open leaky channels, it is thought that a second major consequence of IP 3 R1 cleavage is the formation of IP 3 -independent Ca 2ϩ release channels, which may lead to depletion of the ER Ca 2ϩ store (22,26,27).…”

mentioning

confidence: 99%

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Fragmented Inositol 1,4,5-Trisphosphate Receptors Retain Tetrameric Architecture and Form Functional Ca2+ Release Channels

Alzayady

Chandrasekhar

Yule

2013

Journal of Biological Chemistry

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Background: Proteolytic cleavage and disruption of inositol 1,4,5-trisphosphate receptor (IP 3 R) architecture may contribute to the initiation/progression of apoptosis. Results: Proteolytic cleavage products of the IP 3 R remain membrane-associated, and these fragments form functional tetrameric channels. Conclusion: Fragmentation of the IP 3 R does not inevitably lead to loss of function. Significance: Peptide continuity is not required for IP 3 R function, and IP 3 R activation may persist after protease cleavage during apoptosis.

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Section: Characterizing Ip 3 R1 Fragmentation Patterns During Apoptosis-supporting

confidence: 74%

Section: Characterizing Ip 3 R1 Fragmentation Patterns During Apoptosis-mentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Fragmented Inositol 1,4,5-Trisphosphate Receptors Retain Tetrameric Architecture and Form Functional Ca2+ Release Channels

Alzayady

Chandrasekhar

Yule

2013

Journal of Biological Chemistry

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Type 1 inositol‐1,4,5‐trisphosphate receptor is a late substrate of caspases during apoptosis

Elkoreh

Blais

Béliveau

et al. 2012

J of Cellular Biochemistry

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Apoptosis is characterized by the proteolytic cleavage of hundreds of proteins. One of them, the type 1 inositol-1,4,5-trisphosphate receptor (IP(3) R-1), a multimeric receptor located on the endoplasmic reticulum (ER) membrane that is critical to calcium homeostasis, was reported to be cleaved during staurosporine (STS) induced-apoptosis in Jurkat cells. Because the reported cleavage site separates the IP(3) binding site from the channel moiety, its cleavage would shut down a critical signaling pathway that is common to several cellular processes. Here we show that IP(3) R-1 is not cleaved in 293 cells treated with STS, TNFα, Trail, or ultra-violet (UV) irradiation. Further, it is not cleaved in Hela or Jurkat cells induced to undergo apoptosis with Trail, TNFα, or UV. In accordance with previous reports, we demonstrate that it is cleaved in a Jurkat cell line treated with STS. However its cleavage occurs only after poly(ADP-ribose) polymerase (PARP), which cleavage is a hallmark of apoptosis, and p23, a poor caspase-7 substrate, are completely cleaved, suggesting that IP(3) R-1 is a relatively late substrate of caspases. Nevertheless, the receptor is fully accessible to proteolysis in cellulo by ectopically overexpressed caspase-7 or by the tobacco etch virus (TEV) protease. Finally, using recombinant caspase-3 and microsomal fractions enriched in IP(3) R-1, we show that the receptor is a poor caspase-3 substrate. Consequently, we conclude that IP(3) R-1 is not a key death substrate.

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Role of Caspase-3 Cleaved IP₃R1 on Ca²⁺Homeostasis and Developmental Competence of Mouse Oocytes and Eggs

Zhang

Fissore

2014

J. Cell. Physiol

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Apoptosis in most cell types is accompanied by altered Ca2+ homeostasis. During apoptosis, caspase-3 mediated cleavage of the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) generates a 95-kDa C-terminal fragment (C-IP3R1), which represents the channel domain of the receptor. Aged mouse eggs display abnormal Ca2+ homeostasis and express C-IP3R1, although whether or not C-IP3R1 expression contributes to Ca2+ misregulation or a decrease in developmental competency is unknown. We sought to answer these questions by injecting in mouse oocytes and eggs cRNAs encoding CIP3R1. We found that: 1) expression of C-IP3R1 in eggs lowered the Ca2+ content of the endoplasmic reticulum (ER), although, as C-IP3R1 is quickly degraded at this stage, its expression did not impair pre-implantation embryo development; 2) expression of CIP3R1 in eggs enhanced fragmentation associated with aging; 3) endogenous IP3R1 is required for aging associated apoptosis, as its down-regulation prevented fragmentation, and expression of C-IP3R1 in eggs with downregulated IP3R1 partly restored fragmentation; 4) C-IP3R1 expression in GV oocytes resulted in persistent levels of protein, which abolished the increase in the ER releasable Ca2+ pool that occurs during maturation, undermined the Ca2+ oscillatory ability of matured eggs and their activation potential. Collectively, this study supports a role for IP3R1 and C-IP3R1 in regulating Ca2+ homeostasis and the ER Ca2+ content during oocyte maturation. Nevertheless, the role of C-IP3R1 on Ca2+ homeostasis in aged eggs seems minor, as in MII eggs the majority of endogenous IP3R1 remains intact and C-IP3R1 undergoes rapid turnover.

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Caspase‐3‐truncated type 1 inositol 1,4,5‐trisphosphate receptor enhances intracellular Ca²⁺ leak and disturbs Ca²⁺ signalling

Cited by 48 publications

References 52 publications

Fragmented Inositol 1,4,5-Trisphosphate Receptors Retain Tetrameric Architecture and Form Functional Ca2+ Release Channels

Fragmented Inositol 1,4,5-Trisphosphate Receptors Retain Tetrameric Architecture and Form Functional Ca2+ Release Channels

Type 1 inositol‐1,4,5‐trisphosphate receptor is a late substrate of caspases during apoptosis

Role of Caspase-3 Cleaved IP₃R1 on Ca²⁺Homeostasis and Developmental Competence of Mouse Oocytes and Eggs

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Caspase‐3‐truncated type 1 inositol 1,4,5‐trisphosphate receptor enhances intracellular Ca2+ leak and disturbs Ca2+ signalling

Cited by 48 publications

References 52 publications

Fragmented Inositol 1,4,5-Trisphosphate Receptors Retain Tetrameric Architecture and Form Functional Ca2+ Release Channels

Fragmented Inositol 1,4,5-Trisphosphate Receptors Retain Tetrameric Architecture and Form Functional Ca2+ Release Channels

Type 1 inositol‐1,4,5‐trisphosphate receptor is a late substrate of caspases during apoptosis

Role of Caspase-3 Cleaved IP3R1 on Ca2+Homeostasis and Developmental Competence of Mouse Oocytes and Eggs

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Product

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Caspase‐3‐truncated type 1 inositol 1,4,5‐trisphosphate receptor enhances intracellular Ca²⁺ leak and disturbs Ca²⁺ signalling

Role of Caspase-3 Cleaved IP₃R1 on Ca²⁺Homeostasis and Developmental Competence of Mouse Oocytes and Eggs