title: A new kind of membrane-tethered eukaryotic transcription factor that shares an auto-proteolytic processing mechanism with bacteriophage tail-spike proteins.
abstract: MrfA, a transcription factor that regulates Dictyostelium prestalk cell differentiation, is an orthologue of the metazoan myelin gene regulatory factor (MRF) proteins. We show that the MRFs contain a predicted transmembrane domain, suggesting that they are synthesised as membrane-tethered proteins that are then proteolytically released. We confirm this for MrfA but report a radically different mode of processing from that of paradigmatic tethered transcriptional regulators, which are cleaved within the transmembrane domain by a dedicated protease. Instead, an auto-proteolytic cleavage mechanism, previously only described for the intramolecular chaperone domains of bacteriophage tail-spike proteins, processes MrfA and, by implication, the metazoan MRF proteins. We also present evidence that the auto-proteolysis of MrfA occurs rapidly and constitutively in the ER and that its specific role in prestalk cell differentiation is conferred by the regulated nuclear translocation of the liberated fragment.
authors.affiliation: Department of Biology, Faculty of Agriculture and Life Science, Hirosaki University, Hirosaki, Aomori 036-8561, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Senoo
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Araki
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukuzawa
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Williams
mesh_terms: D000595:Amino Acid Sequence; D001435:Bacteriophages / Q000235:genetics; D002454:Cell Differentiation; D004023:Dictyostelium / Q000235:genetics / Q000254:growth & development*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006026:Glycoside Hydrolases; D008565:Membrane Proteins / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics; D059748:Proteolysis; D014157:Transcription Factors / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism; D017376:Viral Tail Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D018832:Molecular Chaperones; D014157:Transcription Factors; D017376:Viral Tail Proteins; D006026:Glycoside Hydrolases; C083268:tailspike protein, bacteriophage
keywords: Bacteriophage; C-terminal intramolecular chaperone domain (CIMCD); Dictyostelium; Membrane tether; Myelin-gene regulatory factor (MRF); Serine-lysine dyad; Transcription factor
references.citation: Mol Cell. 2000 Dec;6(6):1355-64
references.pmid: 11163209
references.citation: Cell. 2000 Feb 18;100(4):391-8
references.pmid: 10693756
references.citation: Mol Cell. 2000 Dec;6(6):1509-14
references.pmid: 11163223
references.citation: J Biol Chem. 2007 Feb 2;282(5):2821-31
references.pmid: 17158460
references.citation: Development. 1996 Mar;122(3):753-60
references.pmid: 8631253
references.citation: Dev Biol. 2005 Jun 15;282(2):432-41
references.pmid: 15950608
references.citation: Development. 2004 Feb;131(3):513-23
references.pmid: 14729573
references.citation: Curr Opin Genet Dev. 2000 Aug;10(4):363-9
references.pmid: 10889061
references.citation: PLoS Biol. 2013;11(8):e1001624
references.pmid: 23966832
references.citation: Mol Biol Cell. 1999 Nov;10(11):3787-99
references.pmid: 10564271
references.citation: Biochem J. 1970 Sep;119(2):171-4
references.pmid: 5530748
references.citation: Development. 1993 Jun;118(2):353-62
references.pmid: 8223266
references.citation: J Cell Biol. 1998 Aug 10;142(3):735-50
references.pmid: 9700162
references.citation: PLoS Biol. 2013;11(8):e1001625
references.pmid: 23966833
references.citation: Dev Biol. 1982 Sep;93(1):111-8
references.pmid: 7128927
references.citation: FEBS Lett. 1997 Dec 1;418(3):357-62
references.pmid: 9428745
references.citation: Nature. 1995 Feb 23;373(6516):663-4
references.pmid: 7854443
references.citation: Nat Struct Mol Biol. 2010 Feb;17(2):210-5
references.pmid: 20118935
references.citation: Development. 1996 Mar;122(3):761-9
references.pmid: 8631254
references.citation: Int J Dev Biol. 2012;56(5):325-32
references.pmid: 22811266
references.citation: Cell. 2009 Jul 10;138(1):172-85
references.pmid: 19596243
references.citation: Cell. 2000 Sep 1;102(5):577-86
references.pmid: 11007476