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

An Erratum to this article was published on 17 April 2008

Abstract

Cytokines affect a variety of cellular functions, including regulation of cell numbers by suppression of programmed cell death1. Suppression of apoptosis requires receptor signalling through the activation of Janus kinases and the subsequent regulation of members of the B-cell lymphoma 2 (Bcl-2) family. Here we demonstrate that a Bcl-2-family-related protein, Hax1, is required to suppress apoptosis in lymphocytes and neurons. Suppression requires the interaction of Hax1 with the mitochondrial proteases Parl (presenilin-associated, rhomboid-like) and HtrA2 (high-temperature-regulated A2, also known as Omi). These interactions allow Hax1 to present HtrA2 to Parl, and thereby facilitates the processing of HtrA2 to the active protease localized in the mitochondrial intermembrane space. In mouse lymphocytes, the presence of processed HtrA2 prevents the accumulation of mitochondrial-outer-membrane-associated activated Bax, an event that initiates apoptosis. Together, the results identify a previously unknown sequence of interactions involving a Bcl-2-family-related protein and mitochondrial proteases in the ability to resist the induction of apoptosis when cytokines are limiting.

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Figure 1: Loss of Hax1 results in postnatal lethality and neuronal apoptosis.
Figure 2: Hax1 deficiency results in loss of lymphocytes.
Figure 3: Hax1 is required for Parl-mediated processing of HtrA2.
Figure 4: HtrA2 has a role in controlling accumulation of activated Bax in peripheral lymphocytes.

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Acknowledgements

This work was supported by grants from the National Institutes of Health to J.N.I. and the American Lebanese and Syrian Associated Charities (ALSAC) of SJCRH (St Jude Children’s Research Hospital). We thank B. De Strooper for providing reagents and information regarding the properties of the Parl-null mice and L. Pellegrini for antisera against Parl. J.T.O. is a Pew Scholar in the Biomedical Sciences.

Author Contributions J.-R.C. planned the project, performed experimental work and helped to prepare the manuscript. E.P. and C.Y.H. performed experimental work. K.B. performed the animal histology. J.T.O. and J.N.I. planned and directed the project, analysed data and wrote the manuscript.

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Correspondence to James N. Ihle.

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Chao, JR., Parganas, E., Boyd, K. et al. Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons. Nature 452, 98–102 (2008). https://doi.org/10.1038/nature06604

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