Herp Stabilizes Neuronal Ca2+ Homeostasis and Mitochondrial Function during Endoplasmic Reticulum Stress

Abstract

In response to endoplasmic reticulum (ER) stress, cells launch homeostatic and protective responses, but can also activate cell death cascades. A 54 kDa integral ER membrane protein called Herp was identified as a stress-responsive protein in non-neuronal cells. We report that Herp is present in neurons in the developing and adult brain, and that it is regulated in neurons by ER stress; sublethal levels of ER stress increase Herp levels, whereas higher doses decrease Herp levels and induce apoptosis. The endoplasmic reticulum (ER) 1 is a unique cellular compartment simultaneously involved in the processes of protein synthesis and Ca 2ϩ homeostasis. Various conditions, including oxidative and metabolic stress and Ca 2ϩ overload can interfere with ER functions leading to the accumulation of misfolded proteins. Cells sense and respond to such ER stress by activating a signaling cascade termed the unfolded protein response, which results in the transcriptional up-regulation of stress proteins including members of the glucose-regulated protein (grp) family and other protein chaperones (calnexin, calreticulin, ERp72) that enhance the protein folding capability of the ER (1). ER stress has been documented in neurons in a variety of acute pathological conditions including cerebral ischemia and severe epileptic seizures (2). However, despite the fact that disruption of cellular Ca 2ϩ homeostasis contributes to the death of neurons in these conditions, it is not known how molecular responses to ER stress modify cellular Ca 2ϩ homeostasis and the cell death process. Studies of cultured cells suggest that ER stress can stimulate the expression of cytoprotective genes such as protein chaperones (3) but may also trigger a form of programmed cell death called apoptosis (4), which may involve activation of ER-associated caspases and transcription factors such as Gadd153. A better understanding of ER stress and its links to cell survival/death decisions is therefore needed.Recent findings suggest that ER stress is also implicated in several chronic neurodegenerative disorders including Alzheimer's (5, 6), Parkinson's (7), and Huntington's (8) diseases. Alzheimer's disease (AD) results from altered proteolytic processing of the amyloid precursor protein (APP), resulting in aggregation of neurotoxic forms of amyloid ␤-peptide (A␤) (9). Exposure of cultured neurons to A␤-peptide, and metabolic and oxidative insults can induce an ER stress response (6, 10). Moreover, mutations in presenilin-1 (PS1) that cause earlyonset familial AD perturb ER Ca 2ϩ homeostasis (11, 12) and impair the ability of neurons to engage a cytoprotective ER stress response (20). The adverse effects of A␤ and PS1 mutations on ER function may sensitize neurons to excitotoxicity and apoptosis (11).A novel 54 kDa protein called Herp (homocysteine-induced ER protein) was recently identified and characterized as a stress-responsive protein localized in the ER membrane; Herp contains a ubiquitin-like domain and resembles the human DNA excision repair protein hHR23 ...

The CREB3-Herp signalling module limits the cytosolic calcium concentration increase and apoptosis induced by poliovirus

“…CREB3 is produced in large amounts in the CNS (Ying et al, 2014), and Herp has been shown to regulate Ca 2+ homeostasis in neurons and to prevent ER stress-induced apoptosis (Belal et al, 2012;Chan et al, 2004). These findings, together with our results, suggest that the CREB3/ Herp module may be involved in the delicate balance between pro-and anti-apoptotic signals underlying the PVinduced neuropathogenesis of poliomyelitis.…”

“…CREB3 is a transcription factor associated with ER stress and the ERAD pathway through activation of the Herp gene in particular (Asada et al, 2011;Chan et al, 2011;Liang et al, 2006). Herp plays a key role in ER stress recovery (Yan et al, 2014), and regulates Ca 2+ homeostasis in the ER (Belal et al, 2012;Chan et al, 2004).…”

“…It also regulates Ca 2+ homeostasis, by promoting the proteasome-mediated degradation of the Ca 2+ release channels, IP 3 R and RyR (Belal et al, 2012;Chan et al, 2004). Herp is under the transcriptional control of cAMP response element-binding protein 3 (CREB3), a member of the ER membrane-bound CREB/ATF (activating transcription factor) family of proteins, which is rapidly activated in response to cellular stress signals via the Golgi regulated intramembrane proteolysis (RIP) pathway (Asada et al, 2011;Chan et al, 2011;Raggo et al, 2002).…”

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

“…HERP being a membrane protein, considerable effort was dedicated to identification of a suitable solubilization approach facilitating release of HERP from the ER membrane in a form compatible with its capture via His-tagged p40 on Ni 2ϩ -NTAagarose. Three isolation protocols were tested starting from cells treated with thapsigargin, previously shown to significantly up-regulate HERP (33) (Fig. 3, B and C).…”

A Monoclonal Antibody against Human Homocysteine-Induced Endoplasmic Reticulum Protein (Herp): A Useful Tool for Evaluating Endoplasmic Reticulum Stress

“…High expression of Herp with formation of amyloid β -protein deposited in vascular cells was observed in the brains of patients with Alzheimer disease (Sai et al 2002). Herp may regulate neuronal Ca 2+ signaling (Chan et al 2004), and the expression of Herp markedly increased in neurons of rats subjected to ER stress (Hori et al 2004). Herp may play a protective role against ER stress.…”