CREB4, a transmembrane bZip transcription factor and potential new substrate for regulation and cleavage by S1P.
Regulated intramembrane proteolysis of the factors SREBP and ATF6 represents a central control mechanism in sterol homeostasis and stress response within the endoplasmic reticulum. Here, we compare localization of ATF6-related bZip factors CREB4, CREB-H, Luman, and OASIS. These factors contain the defining features of a bZip domain, a predicted transmembrane domain and an adjacent cleavage site for the Golgi protease S1P, with conserved features which indicate that it represents a specific subclass of S1P sites. Each factor localizes to the endoplasmic reticulum (ER), but a population of CREB4 was also observed in the Golgi. Deletion of the transmembrane domain in CREB4 resulted in efficient nuclear accumulation. An N-terminal variant of CREB4 containing the BZIp domain potently activated expression from a target gene containing ATF6 binding sites and from the promoter for the ER chaperone GRP78/BIP. CREB4 was cleaved in a site-specific manner in response to brefeldin A disruption of the Golgi or by coexpression with S1P but only after deletion or substitution of its C-terminal lumenal domain. Thus, S1P cleavage of CREB4 may be suppressed by a determinant in the C-terminal region. Dithiothreitol induced more complete transport of CREB4 to the Golgi, but not cleavage. Together, the data identify at least one additional bZip factor whose localization responds to ER stress, and we propose a model based on these results that indicates additional levels of control of this novel class of transcription factors.
Stirling
Julie
J
Marie Curie Research Institute, Oxted RH8 0TL, United Kingdom.
O'hare
Peter
P
D000595:Amino Acid Sequence; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020126:Brefeldin A / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D043484:Proprotein Convertases / Q000378:metabolism*; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D012697:Serine Endopeptidases / Q000378:metabolism*; D013379:Substrate Specificity
D050976:Basic-Leucine Zipper Transcription Factors; C107941:CREB3 protein, human; C448322:CREB3L4 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D020126:Brefeldin A; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1