HtrA2 Promotes Cell Death through Its Serine Protease Activity and Its Ability to Antagonize Inhibitor of Apoptosis Proteins

Verhagen, A. M. W.; Silke, John; Ekert, Paul G.; Pakusch, Miha; Kaufmann, Hitto; Connolly, Lisa; Day, Catherine L.; Tikoo, Anjali; Burke, Richard; Wrobel, Carolyn N.; Moritz, Robert L.; Simpson, Richard J.; Vaux, David L.

doi:10.1074/jbc.m109891200

Cited by 500 publications

(420 citation statements)

References 35 publications

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“…The present results show a massive release of the mitochondrial proapoptotic effector proteins Smac/DIABLO and Omi/ HtrA2 [40][41][42][43][44][45] into the cytosol during neutrophil apoptosis ( Figure 7). Both proteins are capable of promoting caspase-9 activation by binding to inhibitor of apoptosis proteins (IAPs) 46 and removing, therefore, their inhibitory activity.…”

Section: Discussionmentioning

confidence: 53%

Functional characterization of mitochondria in neutrophils: a role restricted to apoptosis

et al. 2003

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Mitochondria are known to combine life-supporting functions with participation in apoptosis by controlling caspase activity. Here, we report that in human blood neutrophils the mitochondria are different, because they preserve mainly death-mediating abilities. Neutrophil mitochondria hardly participate in ATP synthesis, and have a very low activity of the tested marker enzymes. The presence of mitochondria in neutrophils was confirmed by quantification of mitochondrial DNA copy number, by detection of mitochondrial porin, and by JC-1 measurement of Dw m . During neutrophilic differentiation, HL-60 cells demonstrated a profound cytochrome c depletion and mitochondrial shape change reminiscent of neutrophils. However, blood neutrophils containing extremely low amounts of cytochrome c displayed strong caspase-9 activation during apoptosis, which was also observed in apoptotic neutrophil-derived cytoplasts lacking any detectable cytochrome c. We suggest that other proapoptotic factors such as Smac/DIABLO and HtrA2/Omi, which are massively released from the mitochondria, have an important role in neutrophil apoptosis.

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Section: Discussionmentioning

confidence: 53%

Functional characterization of mitochondria in neutrophils: a role restricted to apoptosis

et al. 2003

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“…17,18 When released into the cytosol after cell death stimuli, however, the processed form interacts with the X chromosome-linked inhibitor-ofapoptosis protein (XIAP) through its processed N-terminal and antagonizes XIAP, resulting in the promotion of caspase activation and apoptosis. 15,16,19 Because both the mitochondrial proteases, PARL and HtrA2, are deeply involved with mitochondrial function and cell death, they may play important roles in cerebral ischemia. In fact, several studies have shown the role of HtrA2 in cerebral ischemia; [20][21][22] however, these studies were focused on the role of HtrA2 released into the cytosol and did not investigate its role in mitochondria.…”

Section: Introductionmentioning

confidence: 99%

The Role of Parl and HtrA2 in Striatal Neuronal Injury After Transient Global Cerebral Ischemia

Yoshioka

Katsu

Sakata

et al. 2013

J Cereb Blood Flow Metab

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The presenilin-associated rhomboid-like (PARL) protein and high temperature requirement factor A2 (HtrA2) are key regulators of mitochondrial integrity and play pivotal roles in apoptosis. However, their roles after cerebral ischemia have not been thoroughly elucidated. To clarify these roles, mice were subjected to transient global cerebral ischemia, and striatal neuronal injury was assessed. Western blot and coimmunoprecipitation analyses revealed that PARL and processed HtrA2 localized to mitochondria, and that PARL was bound to HtrA2 in sham animals. Expression of PARL and processed HtrA2 in mitochondria significantly decreased 6 to 72 hours after ischemia, and the binding of PARL to HtrA2 disappeared after ischemia. In contrast, expression of processed HtrA2 increased 24 hours after ischemia in the cytosol, where HtrA2 was bound to X chromosome-linked inhibitor-ofapoptosis protein (XIAP). Administration of PARL small interfering RNA inhibited HtrA2 processing and worsened ischemic neuronal injury. Our results show that downregulation of PARL after ischemia is a key step in ischemic neuronal injury, and that it decreases HtrA2 processing and increases neuronal vulnerability. In addition, processed HtrA2 released into the cytosol after ischemia contributes to neuronal injury via inhibition of XIAP.

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“…Even though the activity of caspase-7 has not yet been tested in attached and detached IEC-18 cells, we found in the past that activation of caspase-3 does occur upon detachment of these cells (Rosen et al, 2001), suggesting that at least one of the known targets of the IAPs, such as caspase-3, contributes to the execution of anoikis. Effector caspases can be activated by the release of mitochondrial factors, such as cytochrome c, Omi/ HtrA2 and Smac/Diablo into the cytoplasm (Li et al, 1997;Du et al, 2000;Verhagen et al, 2000;Suzuki et al, 2001;Olson and Kornbluth, 2001;Verhagen et al, 2002;Tsujimoto, 2003;Gottfried et al, 2004). Cytochrome c was proposed to be able to activate initiator caspase-9, which can subsequently trigger effector caspase-3 and -7 (Li et al, 1997).…”

Section: Detachment Of Non-malignant Intestinal Epithelial Cells Trigmentioning

confidence: 99%

“…Cytochrome c was proposed to be able to activate initiator caspase-9, which can subsequently trigger effector caspase-3 and -7 (Li et al, 1997). Omi and Smac in turn are capable of activating these caspases by directly binding to the IAPs and neutralizing them (Du et al, 2000;Verhagen et al, 2002). The release of mitochondrial factors following detachment of IEC-18 cells can be anticipated to occur in response to detachmentdependent downregulation of the antiapoptotic protein Bcl-X L (Adams and Cory, 1998), an event that according to our previous studies is at least in part responsible for anoikis of these cells (Rosen et al, 2000).…”

Section: Detachment Of Non-malignant Intestinal Epithelial Cells Trigmentioning

confidence: 99%

Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells

Liu

et al. 2006

Oncogene

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Detachment of normal epithelial cells from the extracellular matrix triggers apoptosis, a phenomenon called anoikis. Conversely, carcinoma cells tend to be relatively more anoikis-resistant than their normal counterparts, and this increased resistance represents a critical feature of the malignant phenotype. Mechanisms that control susceptibility and resistance to anoikis are not fully understood. It is now known that detachment of non-malignant epithelial cells triggers both pro-and antiapoptotic signals, and it is the balance between these signals and the duration of detachment that determine further fate of the cells. Detachment-induced antiapoptotic events delay anoikis and if cells reattach relatively soon after detachment they survive. Direct regulators of apoptosis responsible for this delay of anoikis are unknown. We found that detachment of non-malignant intestinal epithelial cells triggers upregulation of inhibitors of apoptosis protein (IAP) family, such as X-chromosome-linked inhibitor of apoptosis protein and cellular inhibitor of apoptosis-2 (cIAP2). We demonstrated that this upregulation requires detachmentdependent activation of the transcription factor nuclear factor-jB. We further observed that various IAP antagonists accelerate anoikis, indicating that upregulation of the IAPs delays detachment-triggered apoptosis. We conclude that the IAPs are important regulators of the balance between detachment-triggered life and death signals. Perhaps, not by coincidence, these proteins are often upregulated in carcinomas, tumors composed of cells that tend to be anoikis-resistant.

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HtrA2 Promotes Cell Death through Its Serine Protease Activity and Its Ability to Antagonize Inhibitor of Apoptosis Proteins

Cited by 500 publications

References 35 publications

Functional characterization of mitochondria in neutrophils: a role restricted to apoptosis

Functional characterization of mitochondria in neutrophils: a role restricted to apoptosis

The Role of Parl and HtrA2 in Striatal Neuronal Injury After Transient Global Cerebral Ischemia

Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells

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