Luman/CREB3 Induces Transcription of the Endoplasmic Reticulum (ER) Stress Response Protein Herp through an ER Stress Response Element

Abstract

Luman/CREB3 (also called LZIP) is an endoplasmic reticulum (ER) membrane-bound transcription factor which is believed to undergo regulated intramembrane proteolysis in response to cellular cues. We previously found that Luman activates transcription from the unfolded protein response element. Here we report the identification of Herp, a gene involved in ER stress-associated protein degradation (ERAD), as a direct target of Luman. We found that Luman was transcriptionally induced and proteolytically activated by the ER stress inducer thaspsigargin. Overexpression of Luman activated transcription of cellular Herp via ER stress response element II (ERSE-II; ATTGG-N-CCACG) in the promoter region. Mutagenesis studies and chromatin immunoprecipitation assays showed that Luman physically associates with the Herp promoter, specifically the second half-site (CCACG) of ERSE-II. Luman was also necessary for the full activation of Herp during the ER stress response, since Luman small interfering RNA knockdown or functional repression by a dominant negative mutant attenuated Herp gene expression. Like Herp, overexpression of Luman protected cells against ER stress-induced apoptosis. With Luman structurally similar to ATF6 but resembling XBP1 in DNA-binding specificities, we propose that Luman is a novel factor that plays a role in ERAD and a converging point for various signaling pathways channeling through the ER.

ARMET is a Soluble ER Protein Induced by the Unfolded Protein Response via ERSE-II Element

“…The difference between ERSE and ERSE-II may be responsible for the expression patterns of Grp78 and ARMET, although the contribution of other cis-acting elements or mRNA stability cannot be excluded. As luman/ CREB3 was reported to regulate the HERP gene expression in response to ER stress via the ERSE-II element (Liang et al, 2006), this transcription factor may also be involved in ARMET gene expression.…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…In addition to ATF6α, several bZIP TFs located in the ER membrane are regulated by RIP. Those TFs include the cAMP response element-binding protein H (CREBH or CREB3L3) (Zhang et al 2006), old astrocyte specifically induced substance (OASIS) (Kondo et al 2005), BBF2 human homolog on chromosome 7 (BBF2H7) (Kondo et al 2007), transcript induced in spermiogenesis α/β (Tisp40α/β) (Nagamori et al 2005), and Luman/CREB3 (Liang et al 2006a). …”

Herpes simplex virus-1 disarms the unfolded protein response in the early stages of infection

“…Activation of these elements can lead to induction of chaperones, translational attenuation, ER-associated degradation (ERAD) of accumulated proteins, and ultimately cell death by apoptosis (reviewed in Bernales et al 2006;Tabas and Ron 2011;Schroder 2008;Malhotra and Kaufman 2007;Mori 2009). Recently, a family of highly similar basic region leucine zipper (bZIP) proteins exemplified by CREB3/Luman (Liang et al 2006;Raggo et al 2002;Lu et al 1997;Freiman and Herr 1997) has also been implicated in the UPR in specific cell types, including CREB3L1 (Chin et al 2005;Omori et al 2001), CREB3L2 (Storlazzi et al 2003), CREB3L3 (Honma et al 1999), and CREB3L4 (Cao et al 2002;Stirling and O'Hare 2006;Qi et al 2002;Stelzer and Don 2002;Nagamori et al 2005).…”