The ubiquitin‐like domain of Herp is involved in Herp degradation, but not necessary for its enhancement of amyloid β‐protein generation

Sai, Xiaorei; Kokame, Koichi; Shiraishi, Hideo; Kawamura, Yuuki; Miyata, Toshiyuki; Yanagisawa, Katsuhiko; Komano, Hiroto

doi:10.1016/s0014-5793(03)01009-3

Cited by 38 publications

(60 citation statements)

References 30 publications

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“…During the ER stress response, Herp helps to stabilize ER Ca 2ϩ homeostasis (4) and also increases ER folding capacity through ERAD (13). Herp also interacts with presenilins and increases the production of amyloid-␤ (42,43). Since the Luman protein has been evidently found in the neurons of mammalian trigeminal ganglia (25), there may be a functional link between Luman and Herp in the ERAD of neurons.…”

Section: Discussionmentioning

confidence: 99%

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

Liang

Audas

Liu

et al. 2006

Molecular and Cellular Biology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Liang

Audas

Liu

et al. 2006

Molecular and Cellular Biology

Self Cite

121

130

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“…In addition, it has been demonstrated that Herp is able to bind ubiquilin proteins, which have been suggested to mediate shuttling of ubiquitylated substrate proteins to the 26 S proteasome (13,14). Although the N-terminal UBL domain of Herp is necessary neither for the interaction with Hrd1 nor for binding ubiquilins (6,14), it is required for the degradation of Herp itself as well as for Herp-mediated anti-apoptotic effects (7,15).…”

Section: Maturation Of Newly Synthesized Proteins In the Ermentioning

confidence: 99%

Herp Regulates Hrd1-mediated Ubiquitylation in a Ubiquitin-like Domain-dependent Manner

Kny

Standera

Hartmann‐Petersen

et al. 2011

Journal of Biological Chemistry

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Accumulation of aberrant proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response pathway that helps the cell to survive under these stress conditions. Herp is a mammalian ubiquitin domain protein, which is strongly induced by the unfolded protein response. It is involved in ERassociated protein degradation (ERAD) and interacts directly with the ubiquitin ligase Hrd1, which is found in high molecular mass complexes of the ER membrane. Here we present the first evidence that Herp regulates Hrd1-mediated ubiquitylation in a ubiquitin-like (UBL) domain-dependent manner. We found that upon exposure of cells to ER stress, elevation of Herp steady state levels is accompanied by an enhanced association of Herp with pre-existing Hrd1. Hrd1-associated Herp is rapidly degraded and substituted by de novo synthesized Herp, suggesting a continuous turnover of the protein at Hrd1 complexes. Further analysis revealed the presence of multiple Hrd1 copies in a single complex enabling binding of a variable number of Herp molecules. Efficient ubiquitylation of the Hrd1-specific ERAD substrate ␣1-antitrypsin null Hong Kong (NHK) required the presence of the Herp UBL domain, which was also necessary for NHK degradation. In summary, we propose that binding of Herp to Hrd1-containing ERAD complexes positively regulates the ubiquitylation activity of these complexes, thus permitting survival of the cell during ER stress. Maturation of newly synthesized proteins in the ER3 is monitored by a number of complex quality control mechanisms (1). One such pathway is known as the unfolded protein response, which is triggered upon the accumulation of misfolded proteins in the ER (2). Many genes that are induced by the UPR either encode proteins that assist folding or promote ER-associated protein degradation (ERAD). ERAD requires the ubiquitylation of ER-derived substrate proteins at the cytosolic surface of the ER membrane, which is a precondition for their extraction to the cytosol and their degradation by the 26 S proteasome (3).Herp, which is strongly induced by the UPR (4, 5), was shown to be involved in the turnover of ERAD substrates (6 -8) and appears to have an anti-apoptotic effect in the cellular response to ER stress (7, 9). Previously, we found that Herp associates with high molecular mass protein complexes containing derlin-1, p97, and the ubiquitin-protein ligase (E3) Hrd1/synoviolin, which mediate the ubiquitylation of substrate proteins and their retro-translocation to the cytosol (6, 10 -12). In addition, it has been demonstrated that Herp is able to bind ubiquilin proteins, which have been suggested to mediate shuttling of ubiquitylated substrate proteins to the 26 S proteasome (13,14). Although the N-terminal UBL domain of Herp is necessary neither for the interaction with Hrd1 nor for binding ubiquilins (6, 14), it is required for the degradation of Herp itself as well as for Herp-mediated anti-apoptotic effects (7, 15).Here we have analyzed the dynamics of the Herp interaction with Hrd1 and the role...

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“…To cope with ER stress, the cell employs a quality control system named unfolded protein response (UPR) (Kaufman, 1999;Schulze et al, 2005) to attenuate translation and accumulation of misfolded proteins and to increase chaperone expression. HERP (homocysteine-induced ER stress protein) is a chaperone-like protein that is strongly upregulated by ER stress (Kokame et al, 2001;Schröder and Kaufman, 2005) and then rapidly degraded (Hori et al, 2004;Kim et al, 2008;Sai et al, 2003). Unlike other stress-induced cytoplasmic chaperones, HERP is an integral membrane protein with both its N-and C-termini facing the cytoplasm (Nogalska et al, 2006;Sai et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Ube2g2-gp78-mediated HERP polyubiquitination is involved in ER stress recovery

Long

Liu

Zhang

et al. 2014

Journal of Cell Science

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A large number of studies have focused on how individual organisms respond to a stress condition, but little attention has been paid to the stress recovery process, such as the endoplasmic reticulum (ER) stress recovery. Homocysteine-induced ER protein (HERP) was originally identified as a chaperone-like protein that is strongly induced upon ER stress. Here we show that, after ER stress induction, HERP is rapidly degraded by Ube2g2-gp78-mediated ubiquitylation and proteasomal degradation. The polyubiquitylation of HERP in vitro depends on a physical interaction between the CUE domain of gp78 and the ubiquitin-like (UBL) domain of HERP, which is essential for HERP degradation in vivo during ER stress recovery. We further show that although HERP promotes cell survival under ER stress, high levels of HERP expression reduce cell viability under oxidative stress conditions, suggesting that HERP plays a dual role in cellular stress adaptation. Together, these results establish the ubiquitin-proteasome-mediated degradation of HERP as a novel mechanism that fine-tunes the stress tolerance capacity of the cell.

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The ubiquitin‐like domain of Herp is involved in Herp degradation, but not necessary for its enhancement of amyloid β‐protein generation

Cited by 38 publications

References 30 publications

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

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

Herp Regulates Hrd1-mediated Ubiquitylation in a Ubiquitin-like Domain-dependent Manner

Ube2g2-gp78-mediated HERP polyubiquitination is involved in ER stress recovery

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