Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons

Chao, Jung; Parganas, Evan; Boyd, Kelli L.; Hong, Chang Yee; Opferman, Joseph T.; Ihle, James N.

doi:10.1038/nature06604

Cited by 226 publications

(195 citation statements)

References 27 publications

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“…Although mitochondrial insertion of GrB has not been previously reported, a recent seminal study (52) demonstrated the insertion of another granzyme, GrA, into the mitochondrial matrix, when it is applied directly on isolated mitochondria or together with perforin onto target cells. The resistance of Hax-1 to mitochondrial treatment with proteinase K in association with its release from GrB-treated mitochondria are in line with previous reports on the potential localization of Hax-1 on the mitochondrial inner membrane facing the intermembrane space (28). Thus, Hax-1 cross-talk with the mitochondrial matrix protein, Cyp-D, may take place on the mitochondrial inner membrane.…”

Section: Discussionsupporting

confidence: 90%

“…However, compared with fibroblasts from normal donors, stressed Hax-1-deficient fibroblasts from severe congenital neutropenia patients showed a more rapid loss of their membrane potential, suggesting that Hax-1-mediated stabilization of the MMP is not limited to neutrophils (23). Indeed, the likelihood that Hax-1 acts as a mitochondrial antiapoptotic protein in other cells has been verified by a Hax-1-null mouse model (28). Loss of Hax-1 resulted in postnatal lethality as well as lymphocyte and neuron apoptosis.…”

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confidence: 99%

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Deregulation of Mitochondrial Membrane Potential by Mitochondrial Insertion of Granzyme B and Direct Hax-1 Cleavage

Han

Goldstein

Hou

et al. 2010

Journal of Biological Chemistry

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The cytoplasm and the nucleus have been identified as activity sites for granzyme B (GrB) following its delivery from cytotoxic lymphocyte granules into target cells. Here we report on the ability of exogenous GrB to insert into and function within a proteinase K-resistant mitochondrial compartment. We identified Hax-1 (HS-1-associated protein X-1), a mitochondrial protein involved in the maintenance of mitochondrial membrane potential, as a GrB substrate within the mitochondrion. GrB cleaves Hax-1 into two major fragments: an N-terminal fragment that localizes to mitochondria and a C-terminal fragment that localizes to the cytosol after being released from GrBtreated mitochondria. The N-terminal Hax-1 fragment major cellular impact is on the regulation of mitochondrial polarization. Overexpression of wild-type Hax-1 or its uncleavable mutant form protects the mitochondria against GrB or valinomycin-mediated depolarization. The N-terminal Hax-1 fragment functions as a dominant negative form of Hax-1, mediating mitochondrial depolarization in a cyclophilin D-dependent manner. Thus, induced expression of the N-terminal Hax-1 fragment results in mitochondrial depolarization and subsequent lysosomal degradation of such altered mitochondria. This study is the first to demonstrate GrB activity within the mitochondrion and to identify Hax-1 cleavage as a novel mechanism for GrB-mediated mitochondrial depolarization.The granzyme family of serine proteases are pivotal mediators of apoptosis utilized by cytotoxic lymphocytes against targets such as virus-infected cells and tumor cells (1-6). Granzyme B (GrB) 3 exerts its cytotoxic effect after perforin-dependent intracellular delivery, acting in both cytosolic and nuclear compartments. The capacity of GrB to initiate a mitochondrial apoptotic cascade that features permeabilization of the mitochondrial outer membrane and release of apoptogenic proteins has been tied directly to cleavage of Bid (7-10). GrB-generated tBid activates the downstream executioners of the mitochondrial apoptotic cascade, Bax and/or Bak (11). However, mitochondria of Bid-deficient cells continue to release cytochrome c in response to GrB, suggesting the existence of an alternative mechanism(s). Our recent studies demonstrated that GrB induces a mitochondrial apoptotic cascade by cleaving Mcl-1, an antiapoptotic Bcl-2 family member that resides on the mitochondrial outer membrane in a complex with a potent proapoptotic BH3-only protein, Bim. GrB-mediated degradation of Mcl-1 releases sequestered Bim, allowing the execution of a distinct apoptotic cascade (12, 13). The mitochondrial function of BH3-only proteins, including Bid and Bim, is strictly Bax/Bak-dependent (14). Accordingly, Bax/Bak-deficient cells are relatively resistant to GrB-mediated apoptosis, but mitochondria continue to undergo significant depolarization that cannot be attributed to currently described mechanisms of GrB-mediated apoptosis (10,15,16).Mitochondrial polarization (i.e. maintenance of its inner membrane potential) is ulti...

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Deregulation of Mitochondrial Membrane Potential by Mitochondrial Insertion of Granzyme B and Direct Hax-1 Cleavage

Han

Goldstein

Hou

et al. 2010

Journal of Biological Chemistry

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“…However, we could not detect any HAX-1 cleavage product(s) in the current study (the same source of anti-HAX-1 antibody was used). The expression of HAX-1 was recently shown to be regulated by cytokines, suggesting a level of transcriptional control of HAX-1 (26). Moreover, as mentioned in the preceding section, TPCK is known to suppress the transcription factor, NF-B.…”

Section: Hax-1 Down-regulation Occurs At the Transcriptional Level Anmentioning

confidence: 87%

“…HS1 and HAX-1 (HS1-associated protein X-1) are both expressed in B cells, and Suzuki et al (32) speculated that HAX-1 could participate in transduction of the signal from the B cell receptor to intracellular organelles, including mitochondria and endoplasmic reticulum. Furthermore, overexpression of HAX-1 has been reported to block apoptosis in various cell types (14,(22)(23)(24), and homozygous HAX1 deficiency in mice results in postnatal lethality with extensive apoptosis of neurons in the striatum and cerebellum (26). HAX-1 is sometimes classified as a Bcl-2 family protein, based on its structural similarity to Bcl-2 and its mitochondrial localization (32).…”

Section: Discussionmentioning

confidence: 99%

Nα-Tosyl-l-phenylalanine Chloromethyl Ketone Induces Caspase-dependent Apoptosis in Transformed Human B Cell Lines with Transcriptional Down-regulation of Anti-apoptotic HS1-associated Protein X-1

Jitkaew

Trębińska

Grzybowska

et al. 2009

Journal of Biological Chemistry

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was originally synthesized as a specific inhibitor of chymotrypsin-like serine proteases (1) and has been widely used to investigate signal transduction pathways that are involved in gene expression and cell survival/cell death. However, contradictory effects of TPCK on apoptosis have been reported. Hence, TPCK was shown to prevent apoptosis in a cell death stimulus-dependent manner in some model systems (2-4), and a recent study also suggested that TPCK may diminish apoptosis by direct and nonspecific inhibition of active caspases (5). On the other hand, TPCK was also reported to potentiate apoptosis induced by certain apoptotic stimuli, and this was suggested to occur, at least in some cases, through activation of cell cycle checkpoints via inhibition of the proteasome (3, 6). TPCK alone may also induce apoptosis. TPCK thus caused a reduction in activity of the transcription factor, NF-B, in a murine B lymphoma cell line resulting in a decrease in c-myc and activation of apoptosis (7,8). Subsequent studies have shown that TPCK can induce apoptosis in a human acute monocytic leukemia cell line through activation of mitochondria-dependent apoptosis signaling (4, 9). Studies in transformed human T cells also indicated that TPCK can induce apoptosis through inhibition of constitutive NF-B activation, and it was proposed that TPCK might affect sulfhydryl groups on proteins involved in regulating cell survival and NF-B acti- 4 The abbreviations used are: TPCK, N ␣ -tosyl-L-phenylalanine chloromethyl ketone; z, N-benzyloxycarbonyl; fmk, fluoromethyl ketone; AIF, apoptosisinducing factor; cIAP1, cellular inhibitor of apoptosis protein-1; cIAP2, cellular inhibitor of apoptosis protein-2; AMC, 7-amino-4-methylcoumarin; DHE, dihydroethidium; ⌬ m , mitochondrial transmembrane potential; EBV, Epstein-Barr virus; HAX-1, HS1-associated protein X-1; IB, inhibitor of NF-B; NAC, N-acetylcysteine; NF-B, nuclear factor B; PARP, poly(ADPribose) polymerase; PI, propidium iodide; ROS, reactive oxygen species; SCN, severe congenital neutropenia; TMRE, tetramethylrhodamine ethyl ester; XIAP, X chromosome-linked inhibitor of apoptosis protein.

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“…Their development was not obviously perturbed but they present an early neurodegenerative disorder with a parkinsonian phenotype [57]. As for some other IMS proteins, Omi seems to have at least two distinct roles, a physiological anti-apoptotic role via mitochondria protection under some stresses, [58,59] and a death effector role, via the inhibition of IAPs, and also, maybe, via the cleavage of other substrates [56].…”

Section: Contribution Of Momp To Caspase-independent Cell Deathmentioning

confidence: 99%

Mitochondrial control of caspase-dependent and -independent cell death

Pradelli

Bénéteau

Ricci

2010

Cell. Mol. Life Sci.

242

154

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Mitochondria control whether a cell lives or dies. The role mitochondria play in deciding the fate of a cell was first identified in the mid-1990s, because mitochondria-enriched fractions were found to be necessary for activation of death proteases, the caspases, in a cell-free model of apoptotic cell death. Mitochondrial involvement in apoptosis was subsequently shown to be regulated by Bcl-2, a protein that was known to contribute to cancer in specific circumstances. The important role of mitochondria in promoting caspase activation has therefore been a major focus of apoptosis research; however, it is also clear that mitochondria contribute to cell death by caspase-independent mechanisms. In this review, we will highlight recent findings and discuss the mechanism underlying the mitochondrial control of apoptosis and caspase-independent cell death.

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Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons

Cited by 226 publications

References 27 publications

Deregulation of Mitochondrial Membrane Potential by Mitochondrial Insertion of Granzyme B and Direct Hax-1 Cleavage

Deregulation of Mitochondrial Membrane Potential by Mitochondrial Insertion of Granzyme B and Direct Hax-1 Cleavage

Nα-Tosyl-l-phenylalanine Chloromethyl Ketone Induces Caspase-dependent Apoptosis in Transformed Human B Cell Lines with Transcriptional Down-regulation of Anti-apoptotic HS1-associated Protein X-1

Mitochondrial control of caspase-dependent and -independent cell death

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