The Ubiquitin-domain Protein HERP forms a Complex with Components of the Endoplasmic Reticulum Associated Degradation Pathway

Schulze, Andrea; Standera, Sybille; Buerger, Elke; Kikkert, Marjolein; Voorden, Sjaak van; Wiertz, Emmanuel J. H. J.; Koning, Frits; Kloetzel, Peter‐Michael; Seeger, Michael

doi:10.1016/j.jmb.2005.10.020

Cited by 187 publications

(188 citation statements)

References 28 publications

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“…Levels of polyubiquitinated proteins as well as levels of two different subunits of the 26S proteasome, β5 and Rpt2, did not change upon SubAB treatment. There was also no change in the levels of the ubiquitin-like protein HERP involved in ERAD (Hori et al, 2004;Schulze et al, 2005). SubAB induced phosphorylation of eIF2α which peaked 3 h after addition of the toxin, followed by a decrease in eIF2α phosphorylation after 16 h of incubation.…”

Section: Evaluation Of the Different Features Of Er Stress Induced Bymentioning

confidence: 90%

Decreased ER-associated degradation of α-TCR induced by Grp78 depletion with the SubAB cytotoxin

Lass

Kujawa

McConnell

et al. 2008

The International Journal of Biochemistry & Cell Biology

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HeLa cells stably expressing the α chain of T-cell receptor (αTCR), a model substrate of ERAD (ERassociated degradation), were used to analyze the effects of BiP/Grp78 depletion by the SubAB cytotoxin. SubAB induced XBP1 splicing, followed by JNK phosphorylation, eIF2α phosphorylation, upregulation of ATF3/4 and partial ATF6 cleavage. Other markers of ER stress, including elements of ER-associated degradation (ERAD) pathway, as well as markers of cytoplasmic stress, were not induced. SubAB treatment decreased absolute levels of αTCR, which was caused by inhibition of protein synthesis. At the same time, the half-life of αTCR was extended almost fourfold from 70 min to 210 min, suggesting that BiP normally facilitates ERAD. Depletion ofp97/VCP partially rescued SubAB-induced depletion of αTCR, confirming the role of VCP in ERAD of αTCR. It therefore appears that ERAD of αTCR is driven by at least two different ATPase systems located at two sides of the ER membrane, BiP located on the lumenal side, while p97/ VCP on the cytoplasmic side. While SubAB altered cell morphology by inducing cytoplasm vacuolization and accumulation of lipid droplets, caspase activation was partial and subsided after prolonged incubation. Expression of CHOP/GADD153 occurred only after prolonged incubation and was not associated with apoptosis.

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Section: Evaluation Of the Different Features Of Er Stress Induced Bymentioning

confidence: 90%

Decreased ER-associated degradation of α-TCR induced by Grp78 depletion with the SubAB cytotoxin

Lass

Kujawa

McConnell

et al. 2008

The International Journal of Biochemistry & Cell Biology

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“…First, Derlin1 serves as a key factor of the Hrd1 ERAD complex (Fig. 3A) [62,75], which is commonly regarded as the major ERAD activity. In this canonical dislocation route, multiple quality control factors such as Sel1L, which mediates interaction with the luminal lectin OS9 and acts as substrate receptor for soluble ERAD substrates [76], or BAP31, a protein sorting factor for TM cargo [77], collectively deliver ERAD substrates to Derlin1.…”

Section: Physiolgoical and Pathological Roles Of Mammalian Derlinsmentioning

confidence: 99%

Inactive rhomboid proteins: New mechanisms with implications in health and disease

Lemberg

Adrain

2016

Seminars in Cell & Developmental Biology

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Rhomboids, proteases containing an unusual membrane-integral serine protease active site, were first identified in Drosophila, where they fulfill an essential role in epidermal growth factor receptor signaling, by cleaving membrane-tethered growth factor precursors. It has recently become apparent that eukaryotic genomes harbor conserved catalytically inactive rhomboid protease homologs, including derlins and iRhoms. Here we highlight how loss of proteolytic activity was followed in evolution by impressive functional diversification, enabling these pseudoproteases to fulfill crucial roles within the secretory pathway, including protein degradation, trafficking regulation, and inflammatory signaling. We distil the current understanding of the roles of rhomboid pseudoproteases in development and disease.

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“…HERP is required for destruction of a number of proteins via the ERassociated degradation (ERAD) pathway, such as CD3-delta, connexin 43, non-secreted Ig LC, mutant Ig␥ LC, and truncated Ig␥ HC (24 -26). HERP is a component of a larger ERAD retrotranslocation complex comprising the E3 ligase HRD1, Derlin-1, VIMP, and the ATPase p97 (26,27). HERP knock-out also results in increased susceptibility to ER stress-related cell death by thapsigargin, tunicamycin, or A23187 (24).…”

mentioning

confidence: 99%

Inhibition of Secretion of Interleukin (IL)-12/IL-23 Family Cytokines by 4-Trifluoromethyl-celecoxib Is Coupled to Degradation via the Endoplasmic Reticulum Stress Protein HERP

McLaughlin

Alloza

Quoc

et al. 2010

Journal of Biological Chemistry

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Interleukin-12 (IL-12), p80, and IL-23 are structurally related cytokines sharing a p40 subunit. We have recently demonstrated that celecoxib and its COX-2-independent analogue 4-trifluoromethyl-celecoxib (TFM-C) inhibit secretion but not transcription of IL-12 (p35/p40) and p80 (p40/p40). This is associated with a mechanism involving altered cytokine-chaperone interaction in the endoplasmic reticulum (ER). In the present study, we found that celecoxib and TFM-C also block secretion of IL-23 (p40/p19 heterodimers). Given the putative ER-centric mode of these compounds, we performed a comprehensive RT-PCR analysis of 23 ER-resident chaperones/foldases and associated co-factors. This revealed that TFM-C induced 1.5-3-fold transcriptional up-regulation of calreticulin, GRP78, GRP94, GRP170, ERp72, ERp57, ERdj4, and ERp29. However, more significantly, a 7-fold up-regulation of homocysteine-inducible ER protein (HERP) was observed. HERP is part of a high molecular mass protein complex involved in ER-associated protein degradation (ERAD). Using co-immunoprecipitation assays, we show that TFM-C induces protein interaction of p80 and IL-23 with HERP. Both HERP siRNA knockdown and HERP overexpression coupled to cycloheximide chase assays revealed that HERP is necessary for degradation of intracellularly retained p80 by TFM-C. Thus, our data suggest that targeting cytokine folding in the ER by small molecule drugs could be therapeutically exploited to alleviate inappropriate inflammation in autoimmune conditions. The interleukin-12 (IL-12)2 subfamily of cytokines is structurally based around a shared p40 subunit, covalently linked to p35 in IL-12 and to p19 in IL-23. In addition, p40 can be secreted both as a monomer and as a homodimer, named p80. Further members of this family include IL-27, which is a heterodimer consisting of the p40-related protein "Epstein-Barr virus-induced gene 3" (EBI3) and the p35-related subunit p28 and IL-35 (EBI3/p35) (1). IL-12 and IL-23 have been identified at elevated levels in a number of autoimmune diseases, including multiple sclerosis (MS) and its animal model EAE (2, 3

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The Ubiquitin-domain Protein HERP forms a Complex with Components of the Endoplasmic Reticulum Associated Degradation Pathway

Cited by 187 publications

References 28 publications

Decreased ER-associated degradation of α-TCR induced by Grp78 depletion with the SubAB cytotoxin

Decreased ER-associated degradation of α-TCR induced by Grp78 depletion with the SubAB cytotoxin

Inactive rhomboid proteins: New mechanisms with implications in health and disease

Inhibition of Secretion of Interleukin (IL)-12/IL-23 Family Cytokines by 4-Trifluoromethyl-celecoxib Is Coupled to Degradation via the Endoplasmic Reticulum Stress Protein HERP

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