title: DOR/Tp53inp2 and Tp53inp1 constitute a metazoan gene family encoding dual regulators of autophagy and transcription.
abstract: Human DOR/TP53INP2 displays a unique bifunctional role as a modulator of autophagy and gene transcription. However, the domains or regions of DOR that participate in those functions have not been identified. Here we have performed structure/function analyses of DOR guided by identification of conserved regions in the DOR gene family by phylogenetic reconstructions. We show that DOR is present in metazoan species. Invertebrates harbor only one gene, DOR/Tp53inp2, and in the common ancestor of vertebrates Tp53inp1 may have arisen by gene duplication. In keeping with these data, we show that human TP53INP1 regulates autophagy and that different DOR/TP53INP2 and TP53INP1 proteins display transcriptional activity. The use of molecular evolutionary information has been instrumental to determine the regions that participate in DOR functions. DOR and TP53INP1 proteins share two highly conserved regions (region 1, aa residues 28-42; region 2, 66-112 in human DOR). Mutation of conserved hydrophobic residues in region 1 of DOR (that are part of a nuclear export signal, NES) reduces transcriptional activity, and blocks nuclear exit and autophagic activity under autophagy-activated conditions. We also identify a functional and conserved LC3-interacting motif (LIR) in region 1 of DOR and TP53INP1 proteins. Mutation of conserved acidic residues in region 2 of DOR reduces transcriptional activity, impairs nuclear exit in response to autophagy activation, and disrupts autophagy. Taken together, our data reveal DOR and TP53INP1 as dual regulators of transcription and autophagy, and identify two conserved regions in the DOR family that concentrate multiple functions crucial for autophagy and transcription.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Sancho
authors.forename: Jordi
authors.initials: J
authors.lastname: Duran
authors.forename: Antonio
authors.initials: A
authors.lastname: García-España
authors.forename: Caroline
authors.initials: C
authors.lastname: Mauvezin
authors.forename: Endalkachew A
authors.initials: EA
authors.lastname: Alemu
authors.forename: Trond
authors.initials: T
authors.lastname: Lamark
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Macias
authors.forename: Rob
authors.initials: R
authors.lastname: DeSalle
authors.forename: Miriam
authors.initials: M
authors.lastname: Royo
authors.forename: David
authors.initials: D
authors.lastname: Sala
authors.forename: Javier U
authors.initials: JU
authors.lastname: Chicote
authors.forename: Manuel
authors.initials: M
authors.lastname: Palacín
authors.forename: Terje
authors.initials: T
authors.lastname: Johansen
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007448:Invertebrates / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016415:Sequence Alignment; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C429767:TP53INP1 protein, human; C501283:TP53INP2 protein, human