title: Developmental control of apoptosis by the immunophilin aryl hydrocarbon receptor-interacting protein (AIP) involves mitochondrial import of the survivin protein.
abstract: Survivin is a multifunctional protein with essential roles in cell division and inhibition of apoptosis, but the molecular underpinnings of its cytoprotective properties are poorly understood. Here we show that homozygous deletion of the aryl hydrocarbon receptor-interacting protein (AIP), a survivin-associated immunophilin, causes embryonic lethality in mice by embryonic day 13.5-14, increased apoptosis of Ter119(-)/CD71(-) early erythropoietic progenitors, and loss of survivin expression in its cytosolic and mitochondrial compartments in vivo. In import assays using recombinant proteins, AIP directly mediated the import of survivin to mitochondria, thus enabling its anti-apoptotic function, whereas a survivin 1-141 mutant that does not bind AIP was not imported to mitochondria and failed to inhibit apoptosis. AIP-directed mitochondrial import of survivin did not affect cell division, was independent of the organelle transmembrane potential, did not require the chaperone Heat Shock Protein 90 (Hsp90), and was inhibited by cytosolic factor(s) present in normal cells. shRNA knockdown of the mitochondrial import receptor Tom20 abolished mitochondrial import of survivin and sensitized tumor cells to apoptosis, whereas silencing of Tom70 had no effect. Therefore, an AIP-Tom20 recognition contributes to cell survival in development and cancer by mediating the mitochondrial import of survivin.
authors: Prostate Cancer Discovery and Development Program, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors: Byoung Heon
authors: BH
authors: Kang
authors: Fang
authors: F
authors: Xia
authors: Ramona
authors: R
authors: Pop
authors: Takehiko
authors: T
authors: Dohi
authors: Merav
authors: M
authors: Socolovsky
authors: Dario C
authors: DC
authors: Altieri
mesh_terms: D000818:Animals; D017209:Apoptosis; D001692:Biological Transport; D003600:Cytosol / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D012097:Repressor Proteins / Q000378:metabolism*; D000077022:Survivin; D013997:Time Factors
chemical_list: C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; D018841:HSP90 Heat-Shock Proteins; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D012097:Repressor Proteins; D000077022:Survivin; C402118:TOMM70 protein, human; C559261:Tom70 protein, mouse; C103265:aryl hydrocarbon receptor-interacting protein