Adaptation to endoplasmic reticulum (ER) stress depends on the activation of an integrated signal transduction pathway known as the unfolded protein response (UPR). Bax inhibitor-1 (BI-1) is an evolutionarily conserved ER-resident protein that suppresses cell death. Here we have investigated the role of BI-1 in the UPR. BI-1 expression suppressed IRE1α activity in fly and mouse models of ER stress. BI-1 deficient cells displayed hyperactivation of the ER stress sensor IRE1α, leading to increased levels of its downstream target X-Box binding protein-1 (XBP-1) and upregulation of UPR target genes. This phenotype was associated with the formation of a stable protein complex between BI-1 and IRE1α, decreasing its ribonuclease activity. Finally, BI-1 deficiency increased the secretory activity of primary B cells, a phenomenon regulated by XBP-1. Our results suggest a new role for BI-1 in early adaptive responses against ER stress which contrasts with its known downstream function in apoptosis.

Endoplasmic reticulum (ER) stress is a common feature of several physiological and pathological conditions affecting the function of the secretory pathway. To restore ER homeostasis, an orchestrated signaling pathway is engaged that is known as the unfolded protein response (UPR). The UPR has a primary function in stress adaptation and cell survival; however, under irreversible ER stress a switch to pro-apoptotic signaling events induces apoptosis of damaged cells. The mechanisms that initiate ER stress-dependent apoptosis are not fully understood. Several pathways have been described where we highlight the participation of the BCL-2 family of proteins and ER calcium release. In addition, recent findings also suggest that microRNAs and oxidative stress are relevant players on the transition from adaptive to cell death programs. Here we provide a global and integrated overview of the signaling networks that may determine the elimination of a cell under chronic ER stress. This article is part of a Special Section entitled: Cell Death Pathways.

The cytosolic chaperone Hsp72 directly modulates stress sensing in response to the accumulation of unfolded proteins in the endoplasmic reticulum and promotes cell survival.

The unfolded protein response (UPR) is a conserved adaptive reaction that increases cell survival under conditions of endoplasmic reticulum (ER) stress. The UPR controls diverse processes such as protein folding, secretion, ER biogenesis, protein quality control and macroautophagy. Occurrence of chronic ER stress has been extensively described in neurodegenerative conditions linked to protein misfolding and aggregation, including Amyotrophic lateral sclerosis, Prion-related disorders, and conditions such as Parkinson's, Huntington's, and Alzheimer's disease. Strong correlations are observed between disease progression, accumulation of protein aggregates, and induction of the UPR in animal and in vitro models of neurodegeneration. In addition, the first reports are available describing the engagement of ER stress responses in brain post-mortem samples from human patients. Despite such findings, the role of the UPR in the central nervous system has not been addressed directly and its contribution to neurodegeneration remains speculative. Recently, however, pharmacological manipulation of ER stress and autophagy - a stress pathway modulated by the UPR - using chemical chaperones and autophagy activators has shown therapeutic benefits by attenuating protein misfolding in models of neurodegenerative disease. The most recent evidence addressing the role of the UPR and ER stress in neurodegenerative disorders is reviewed here, along with therapeutic strategies to alleviate ER stress in a disease context.

Neurotrophins are trophic factors that regulate important neuronal functions. They bind two unrelated receptors, the Trk family of receptor-tyrosine kinases and the p75 neurotrophin receptor (p75). p75 was recently identified as a new substrate for ␥-secretase-mediated intramembrane proteolysis, generating a p75-derived intracellular domain (p75-ICD) with signaling capabilities. Using PC12 cells as a model, we studied how neurotrophins activate p75 processing and where these events occur in the cell. We demonstrate that activation of the TrkA receptor upon binding of nerve growth factor (NGF) regulates the metalloprotease-mediated shedding of p75 leaving a membranebound p75 C-terminal fragment (p75-CTF). Using subcellular fractionation to isolate a highly purified endosomal fraction, we demonstrate that p75-CTF ends up in endosomes where ␥-secretase-mediated p75-CTF cleavage occurs, resulting in the release of a p75-ICD. Moreover, we show similar structural requirements for ␥-secretase processing of p75 and amyloid precursor protein-derived CTFs. Thus, NGF-induced endocytosis regulates both signaling and proteolytic processing of p75.Neurotrophins belong to a small family of neurotrophic factors that include nerve growth factor (NGF), 4 brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin-4 (NT4). They regulate different aspects of the developing and adult nervous system by binding to specific members of the Trk family of receptor-tyrosine kinases (TrkA, -B, and -C) or to the p75 neurotrophin receptor (p75). Their involvement includes neuronal migration, cell death, axonal elongation, myelinization, neuronal differentiation, and synaptic plasticity (1-3). p75 is a multifunctional type I transmembrane protein that is structurally related to the tumor necrosis factor receptor superfamily. It binds all neurotrophins, alone or in complex with Trk receptors, but also other ligands such as amyloid peptides and pro-neurotrophins (4, 5). The association of p75 with different receptors shapes the outcome of a signaling event. For example, binding of p75 to TrkA in the presence of NGF promotes neuronal survival, whereas interaction with the Nogo receptor (NgR) in the presence of its ligands, such as Nogo and myelin-associated glycoprotein (MAG), results in growth cone collapse and the inhibition of axonal regeneration (1, 4, 5). In addition, different downstream p75-associated signaling cascades are triggered through the interaction of its cytosolic portion with multiple adaptor proteins (6). Neurotrophin binding to p75 also induces accumulation of p75 in recycling endosomes where it associates with specific p75 downstream signaling effectors (7-9). Hence trafficking of p75 in the cell body or in axons (10, 11) may determine downstream signaling of p75 as previously shown for Trk receptors (12). The regulation of p75 signaling becomes even more complicated with the finding that p75 is subject to a dual processing starting with shedding of the ectodomain and followed by ␥-secretase cleavage. Thi...