Editors' ChoiceApoptosis

Mitochondrial Proteases Required for Survival

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Science Signaling  11 Mar 2008:
Vol. 1, Issue 10, pp. ec94
DOI: 10.1126/stke.110ec94

The mitochondria are key players in mediating cell death or survival. The release of mitochondrial proteases contributes to cell death during apoptosis. However, knockout of genes encoding the mitochondrial proteases HtrA2 or Parl results in increased susceptibility to apoptosis of lymphocytes and neurons; thus, the function of these enzymes in cell death and survival is complex. Chao et al. screened for genes that suppressed apoptosis of fetal liver cells null for Janus kinase 2 and identified the gene Hax1, which encodes an antiapoptotic protein that is localized to the mitochondrial intermembrane space through a C-terminal transmembrane domain and that has BH1- and BH2-like domains, which make it related to Bcl-2 proteins. When the gene was disrupted in mice, the phenotype, loss of lymphocytes and neurodegeneration in the striatum and cerebellar cortex, was similar to the phenotype of mice lacking functional HtrA2 or Parl. Thus, the authors investigated whether these three proteins have a functional interaction that is important for setting the threshold for apoptosis. Hax1 and HtrA2 had been previously reported to interact in a yeast two-hybrid screen. HtrA2 is synthesized as an inactive precursor that is cleaved within the mitochondria to produce the active form. Chao et al. found that the abundance of processed HtrA2 was decreased in Hax1-null mouse tissues. Furthermore, when COS-7 cells were transfected with both HtrA2 and Hax1 or with HtrA2 and Parl, the abundance of processed HtrA2 was increased compared with that in cells only transfected with HtrA2. In addition, coimmunoprecipitation experiments with endogenous proteins or those from transfected cells showed that Hax1 interacted with both HtrA2 and Parl. Thus, the authors suggest that Hax1 aids in the presentation of HtrA2 to Parl for processing and activation. How this affects apoptosis was the next question. Although knockout of Bax, Bak, or Bim (genes encoding proapoptotic Bcl-2 proteins) did not alleviate the neurodegeneration found in the Hax1-deficient animals, knockout of Bax or Bim did rescue Hax1-deficient lymphocytes from cell death induced by cytokine withdrawal. Activated T cells that were deficient in Hax1 or that had a mutated HtrA2 with disrupted protease activity showed faster kinetics for the appearance of the activated form of Bax, an event associated with apoptosis. Thus, the proteins of the intermembrane space appear to contribute to regulation of apoptosis before mitochondrial membrane permeabilization.

J.-R. Chao, E. Parganas, K. Boyd, C. Y. Hong, J. T. Opferman, J. N. Ihle, Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons. Nature 452, 98-102 (2008). [PubMed]

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