Erratum: 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.

doi:10.1038/nature06872

Cited by 29 publications

(54 citation statements)

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“…In lymphocytes, the presence of HtrA2 prevents accumulation of activated Bax in the mitochondrial outermembrane, which would initiate cytochrome c release and cell death. 12 Moisoi et al 30 showed that HtrA2 is necessary for preventing accumulation of unfolded protein and oxidative stress in mitochondria. A recent study by Li et al 31 reported that HtrA2 is responsible for the maintenance of constitutive autophagy, which can eliminate damaged mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…12,13 However, the processing mechanism is obscure. According to the report by Chao et al, 12 HS1-associated protein X-1 (HAX-1) is required for PARL-mediated processing of HtrA2.…”

Section: Discussionmentioning

confidence: 99%

“…11 In addition, recent studies revealed that PARL participates in the processing of high temperature requirement factor A2 (HtrA2) in mitochondria. 12,13 The HtrA2, also known as Omi, is a mammalian homolog of the bacterial heat-inducible serine protease known as HtrA 14,15 and is synthesized in the nucleus as a precursor containing a mitochondrial target sequence. When imported into mitochondria, it is processed to a mature form and resides in the intermembrane space.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…12,13 However, the processing mechanism is obscure. According to the report by Chao et al, 12 HS1-associated protein X-1 (HAX-1) is required for PARL-mediated processing of HtrA2.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…It was previously reported that a deletion mutant of Omi (DOBS, D-Omi binding sequence, amino acids 201-213) could not bind to Omi. 24 We therefore tested the effects of this mutant on autophagy. Hax-1-EGFP DOBS retained its ability to bind to Beclin-1, whereas it failed to interact with Omi (Figure 4l).…”

Section: Resultsmentioning

confidence: 99%

“…It is worth noting that Hax-1 functions not only as a substrate of Omi, but also as a regulator of the mitochondrial import of Omi through presentation of Omi to another mitochondrial protease, Parl. 24 The loss of lymphocytes in response to certain stresses such as cytokine withdrawal was observed in both Hax-1-null mice and mnd2 mice. 24 Cell death induced by ER ( Figure 5) and mitochondrial stress 7 was also enhanced in mnd2 cells.…”

Section: Discussionmentioning

confidence: 99%

Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases

Wang

et al. 2010

Cell Death Differ

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Omi, also known as high temperature requirement factor A2 (HtrA2), is a serine protease that was originally identified as a proapoptotic protein. Like Smac/Diablo, it antagonizes inhibitor of apoptosis proteins when released into the cytosol on apoptotic stimulation. Loss of its protease activity in mnd2 (motor neuron degeneration 2) mice is associated with neurodegeneration. However, the detailed mechanisms by which Omi regulates the pathogenesis of neurodegenerative disease remain largely unknown. We report here that Omi participates in the pivotal cellular degradation process known as autophagy. It activates autophagy through digestion of Hax-1, a Bcl-2 family-related protein that represses autophagy in a Beclin-1 (mammalian homologue of yeast ATG6)-dependent pathway. Moreover, Omi-induced autophagy facilitates the degradation of neurodegenerative proteins such as pathogenic A53T a-synuclein and truncated polyglutamine-expanded huntingtin, as well as the endogenous autophagy substrate p62. Knockdown of Omi decreases the basal level of autophagy and increases the level of the above target proteins. Furthermore, S276C Omi, the protease-defective mutant found in mnd2 mice, fails to regulate autophagy. Increased autophagy substrates and the formation of aggregate structures are observed in the brains of mnd2 mice. These results identify Omi as a novel regulator of autophagy and suggest that Omi might be important in the cellular quality control of proteins involved in neurodegenerative diseases.

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HAX1 deficiency: Impact on lymphopoiesis and B‐cell development

et al. 2010

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HAX1 was originally described as HS1-associated protein with a suggested function in receptor-mediated apoptotic and proliferative responses of lymphoid cells. Recent publications refer to a complex and multifunctional role of this protein. To investigate the in vivo function of HAX1 (HS1-associated protein X1) in B cells, we generated a Hax1-deficient mouse strain. Targeted deletion of Hax1 resulted in premature death around the age of 12 wk accompanied by a severe reduction of lymphocytes in spleen, thymus and bone marrow. In the bone marrow, all B-cell populations were lost comparably. In the spleen, B220 1 cells were reduced by almost 70%. However, as investigated by adoptive transfer experiments, this impairment is not exclusively B-cell intrinsic and we hypothesize that a HAX1-deficient environment cannot sufficiently provide the essential factors for proper lymphocyte development, trafficking and survival. Hax1 À/À B cells show a significantly reduced expression of CXCR4, which might have an influence on the observed defects in B-cell development.

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

Cited by 29 publications

References 1 publication

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

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

Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases

HAX1 deficiency: Impact on lymphopoiesis and B‐cell development

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