An orchestrated program regulating secretory pathway genes and cargos by the transmembrane transcription factor CREB-H

Traffic. 2013 Apr;14(4):382-98. doi: 10.1111/tra.12038. Epub 2013 Jan 24.


CREB3 proteins comprise a set of ER-localized bZip transcription factors defined by the presence of a transmembrane domain. They are regulated by inter-compartmental transport, Golgi cleavage and nuclear transport where they promote appropriate transcriptional responses. Although CREB3 proteins play key roles in differentiation, inflammation and metabolism, a general framework relating their defining features to these diverse activities is lacking. We identify unique features of CREB3 organization including the ATB domain, which we show it is essential for transcriptional activity. This domain is absent in all other human bZip factors, but conserved in Drosophila CREBA, which controls secretory pathway genes (SPGs). Furthermore, each of the five human CREB3 factors was capable of activating SPGs in Drosophila, dependent upon the ATB domain. Expression of the CREB3 protein, CREB-H, in 293 cells, upregulated genes involved in secretory capacity, extracellular matrix formation and lipid metabolism and increased secretion of specific cargos. In liver cells, which normally express CREB-H, the active form specifically induced secretion of apolipoproteins, including ApoA-IV, ApoAI, consistent with data implicating CREB-H in metabolic homeostasis. Based on these data and other recent studies, we propose a general role for the CREB3 family in regulating secretory capacity, with particular relevance to specialized cargos.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apolipoproteins / metabolism
  • Cell Membrane / metabolism
  • Cyclic AMP Response Element-Binding Protein / chemistry
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Cyclic AMP Response Element-Binding Protein A / chemistry
  • Cyclic AMP Response Element-Binding Protein A / genetics
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics
  • Extracellular Matrix / metabolism
  • Gene Expression Regulation*
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Lipid Metabolism
  • Protein Structure, Tertiary
  • Secretory Pathway / genetics*
  • Sequence Deletion
  • Transcription, Genetic


  • Apolipoproteins
  • CrebA protein, Drosophila
  • Cyclic AMP Response Element-Binding Protein
  • Cyclic AMP Response Element-Binding Protein A
  • Drosophila Proteins