title: Hax1 lacks BH modules and is peripherally associated to heavy membranes: implications for Omi/HtrA2 and PARL activity in the regulation of mitochondrial stress and apoptosis.
abstract: Hax1 has an important role in immunodeficiency syndromes and apoptosis. A recent report (Chao et al., Nature, 2008) proposed that the Bcl-2-family-related protein, Hax1, suppresses apoptosis in lymphocytes and neurons through a mechanism that involves its association to the inner mitochondrial membrane rhomboid protease PARL, to proteolytically activate the serine protease Omi/HtrA2 and eliminate active Bax. This model implies that the control of cell-type sensitivity to pro-apoptotic stimuli is governed by the PARL/Hax1 complex in the mitochondria intermembrane space and, more generally, that Bcl-2-family-related proteins can control mitochondrial outer-membrane permeabilization from inside the mitochondrion. Further, it defines a novel, anti-apoptotic Opa1-independent pathway for PARL. In this study, we present evidence that, in vivo, the activity of Hax1 cannot be mechanistically coupled to PARL because the two proteins are confined in distinct cellular compartments and their interaction in vitro is an artifact. We also show by sequence analysis and secondary structure prediction that Hax1 is extremely unlikely to be a Bcl-2-family-related protein because it lacks Bcl-2 homology modules. These results indicate a different function and mechanism of Hax1 in apoptosis and re-opens the question of whether mammalian PARL, in addition to apoptosis, regulates mitochondrial stress response through Omi/HtrA2 processing.
authors.affiliation: Mitochondria Biology Laboratory, CRULRG, Université Laval, Quebec, QC, Canada G1J 2G3.
authors.forename: D V
authors.initials: DV
authors.lastname: Jeyaraju
authors.forename: G
authors.initials: G
authors.lastname: Cisbani
authors.forename: O M
authors.initials: OM
authors.lastname: De Brito
authors.forename: E V
authors.initials: EV
authors.lastname: Koonin
authors.forename: L
authors.initials: L
authors.lastname: Pellegrini
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D017124:Conserved Sequence; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C104759:HAX1 protein, human; C491295:Hs1bp1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D045726:Metalloproteases; D012697:Serine Endopeptidases; C485223:PARL protein, human; C512710:PARL protein, mouse; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse
references.citation: Dev Cell. 2001 Oct;1(4):515-25
references.pmid: 11703942
references.citation: J Mol Biol. 2000 Sep 8;302(1):205-17
references.pmid: 10964570
references.citation: Cell Death Differ. 2008 Mar;15(3):453-60
references.pmid: 18174901
references.citation: Cell. 2006 Jul 14;126(1):163-75
references.pmid: 16839884
references.citation: Biochim Biophys Acta. 2009 Nov;1787(11):1363-73
references.pmid: 19138660
references.citation: Curr Mol Med. 2008 Mar;8(2):131-7
references.pmid: 18336293
references.citation: J Mol Biol. 2007 Mar 16;367(1):65-79
references.pmid: 17241641
references.citation: Nature. 2008 Mar 6;452(7183):98-102
references.pmid: 18288109
references.citation: Science. 2001 Feb 16;291(5507):1279-84
references.pmid: 11181990
references.citation: Cell. 2006 Jul 14;126(1):177-89
references.pmid: 16839885
references.citation: Trends Cell Biol. 2007 Oct;17(10):511-7
references.pmid: 17851078
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):1883-8
references.pmid: 15684070
references.citation: Nature. 2008 Dec 4;456(7222):605-10
references.pmid: 19052620
references.citation: J Virol. 2002 Jan;76(2):802-16
references.pmid: 11752170
references.citation: Cell. 2008 Jul 11;134(1):112-23
references.pmid: 18614015
references.citation: Cell Death Differ. 2009 Mar;16(3):449-64
references.pmid: 19023330
references.citation: Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W197-201
references.pmid: 18463136
references.citation: Cell. 2008 Dec 12;135(6):1074-84
references.pmid: 19062087
references.citation: Semin Cancer Biol. 2009 Feb;19(1):4-11
references.pmid: 19101633
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18562-7
references.pmid: 17116872
references.citation: Bioinformatics. 2000 Apr;16(4):404-5
references.pmid: 10869041
references.citation: Dev Cell. 2008 Sep;15(3):341-343
references.pmid: 18804432
references.citation: Nat Genet. 2007 Jan;39(1):86-92
references.pmid: 17187068
references.citation: J Cell Biol. 1999 Mar 8;144(5):883-9
references.pmid: 10085288
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W327-31
references.pmid: 15215404
references.citation: Cell Death Differ. 2006 Aug;13(8):1291-5
references.pmid: 16763618
references.citation: Proc Int Conf Intell Syst Mol Biol. 1998;6:175-82
references.pmid: 9783223
references.citation: Nat Rev Cancer. 2005 Nov;5(11):857-66
references.pmid: 16327764
references.citation: Trends Biochem Sci. 2001 Feb;26(2):112-7
references.pmid: 11166569
references.citation: Curr Opin Struct Biol. 2005 Aug;15(4):378-86
references.pmid: 16043344
references.citation: Biochim Biophys Acta. 2004 Mar 1;1644(2-3):83-94
references.pmid: 14996493
references.citation: J Cell Biol. 2008 Dec 1;183(5):795-803
references.pmid: 19029340
references.citation: Int J Biochem Cell Biol. 2009 Oct;41(10):1884-9
references.pmid: 19439192
references.citation: Int J Biochem Cell Biol. 2009 Oct;41(10):1875-83
references.pmid: 19393761
references.citation: Cell Death Differ. 2007 Jul;14(7):1261-6
references.pmid: 17464321
references.citation: Nat Rev Mol Cell Biol. 2008 Jan;9(1):47-59
references.pmid: 18097445
references.citation: Cell Death Differ. 2006 Aug;13(8):1409-18
references.pmid: 16729032
references.citation: Oncogene. 2006 Aug 7;25(34):4675-82
references.pmid: 16892081
references.citation: Biochim Biophys Acta. 2008 Apr;1783(4):610-7
references.pmid: 17996737
references.citation: Nucleic Acids Res. 2003 Jan 1;31(1):383-7
references.pmid: 12520028
references.citation: Genes Dev. 2006 Nov 15;20(22):3054-68
references.pmid: 17114579
references.citation: Cell Death Differ. 2007 Jul;14(7):1275-84
references.pmid: 17464328
references.citation: Genome Biol. 2003;4(3):R19
references.pmid: 12620104
references.citation: Sci STKE. 2004 Jan 13;2004(215):re1
references.pmid: 14722345
references.citation: Sci STKE. 2003 Mar 11;2003(173):pe10
references.pmid: 12631689
references.citation: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references.pmid: 9254694
references.citation: Nat Protoc. 2007;2(2):287-95
references.pmid: 17406588
references.citation: Cell Death Differ. 2007 Jul;14(7):1267-74
references.pmid: 17431419
references.citation: Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):808-16
references.pmid: 18573473
references.citation: Arch Biochem Biophys. 2009 Apr 1;484(1):46-54
references.pmid: 19161970
references.citation: Dev Cell. 2002 Jan;2(1):55-67
references.pmid: 11782314
references.citation: Blood. 2004 May 1;103(9):3355-61
references.pmid: 14764541
references.citation: Annu Rev Genet. 2008;42:191-210
references.pmid: 18605900
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W321-6
references.pmid: 15215403
references.citation: Biochim Biophys Acta. 2006 May-Jun;1763(5-6):442-9
references.pmid: 16750865
references.citation: J Biol Chem. 2004 Apr 9;279(15):15323-9
references.pmid: 14732705
references.citation: Genome Res. 2007 Nov;17(11):1634-46
references.pmid: 17938163
references.citation: Eur J Biochem. 1996 Nov 1;241(3):779-86
references.pmid: 8944766
references.citation: Oncogene. 2004 Apr 12;23(16):2850-60
references.pmid: 15077148