title: MLF1 is a proapoptotic antagonist of HOP complex-mediated survival.
abstract: In the HAX1/HtrA2-OMI/PARL (HOP) mitochondrial protein complex, anti-apoptotic signals are generated by cleavage and activation of the serine protease HtrA2/OMI by the rhomboid protease PARL upon recruitment of both proteases to inner mitochondrial membrane protein HAX1 (HS1-associated protein X-1). Here we report the negative regulation of the HOP complex by human leukemia-associated myeloid leukemia factor 1 (MLF1). We demonstrate that MLF1 physically and functionally associates with HAX1 and HtrA2. Increased interaction of MLF1 with HAX1 and HtrA2 displaces HtrA2 from the HOP complex and inhibits HtrA2 cleavage and activation, resulting in the apoptotic cell death. Conversely, over-expressed HAX1 neutralizes MLF1's effect and inhibits MLF1-induced apoptosis. Importantly, Mlf1 deletion reverses B- and T-cell lymphopenia and significantly ameliorates the progressive striatal and cerebellar neurodegeneration observed in Hax1-/-mice, with a doubling of the lifespan of Mlf1-/-/Hax1-/-animals compared to Hax1-/-animals. Collectively, these data indicate that MLF1 serves as a proapoptotic antagonist that interacts with the HOP mitochondrial complex to modulate cell survival.
authors.affiliation: Department of Oncology, ShiJiaZhuangShi First Hospital, 36 FanXiLu, ShiJiaZhuangShi, Hebei 050011, PR China; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA. Electronic address: yisun456@yahoo.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Jyh-Rong
authors.initials: JR
authors.lastname: Chao
authors.affiliation: Department of Chemistry, University of Louisiana at Lafayette, Lafayette, LA 70504, USA.
authors.forename: Wu
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Pourpak
authors.affiliation: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Kelli
authors.initials: K
authors.lastname: Boyd
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Moshiach
authors.affiliation: Department of Oncology, ShiJiaZhuangShi First Hospital, 36 FanXiLu, ShiJiaZhuangShi, Hebei 050011, PR China.
authors.forename: Guo-Yan
authors.initials: GY
authors.lastname: Qi
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Amina
authors.initials: A
authors.lastname: Fu
authors.affiliation: Department of Orthopaedics, ShiJiaZhuangShi First Hospital, 36 FanXiLu, ShiJiaZhuangShi, Hebei 050011, PR China.
authors.forename: Hua-Rong
authors.initials: HR
authors.lastname: Shao
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Pounds
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Morris
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D018797:Cell Cycle Proteins; D002470:Cell Survival; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020014:K562 Cells; D008231:Lymphopenia / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D045726:Metalloproteases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C491295:Hs1bp1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; C484412:Mlf1 protein, mouse; D011506:Proteins; D045726:Metalloproteases; D012697:Serine Endopeptidases; C512710:PARL protein, mouse; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse
keywords: Apoptosis; HS1-associated protein X-1; Myeloid leukemia factor 1; Neurodegeneration