Different mechanisms of recognition and ER retention by transmembrane transcription factors CREB-H and ATF6

Marta Llarena, Daniel Bailey, Helen Curtis, Peter O. Hare*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


CREB-H and activating transcription factor 6 (ATF6) are transmembrane transcription factors that, in response to endoplasmic reticulum (ER) stress, traffic to the Golgi where they are cleaved by specific proteases, producing the N-terminal domains that effect appropriate transcriptional responses. We show that unlike in ATF6 whose lumenal tail binds BiP and contains determinants for stress sensing and Golgi transport, in CREB-H the lumenal tail is not involved in ER retention, not required for Golgi transport and does not bind BiP. The main determinant for CREB-H ER retention resides in a membrane-proximal cytoplasmic determinant that is conserved in related members of the CREB-H family, but lacking in ATF6. We refine requirements within the ER-retention motif (ERM) and show that ERM-ve variants exhibited constitutive Golgi localization and constitutive cleavage by the Golgi protease, S1P. The ERM also conferred ER retention on a heterologous protein. Furthermore, deletion of the lumenal tail of CREB-H had no effect on ER retention of parental CREB-H or Golgi localization of ERM-ve variants. Importantly, when the lumenal tail of ATF6 was transferred into an ERM-ve variant, the chimera was now retained in the ER. Together, these data demonstrate novel and qualitatively distinct mechanisms of trafficking and stress signalling in CREB-H compared to ATF6.

Original languageEnglish
Pages (from-to)48-69
Number of pages22
Issue number1
Publication statusPublished - Jan 2010
Externally publishedYes


  • ATF6
  • CREB-H
  • CREB3L3
  • ERAD
  • Golgi
  • Proteasome
  • Retrotranslocation
  • Site 1 protease
  • Site 2 protease


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