Recent advances in signal integration mechanisms in the unfolded protein response [version 1; peer review: 2 approved]

Since its discovery more than 25 years ago, great progress has been made in our understanding of the unfolded protein response (UPR), a homeostatic mechanism that adjusts endoplasmic reticulum (ER) function to satisfy the physiological demands of the cell. However, if ER homeostasis is unattainable, the UPR switches to drive cell death to remove defective cells in an effort to protect the health of the organism. This functional dichotomy places the UPR at the crossroads of the adaptation versus apoptosis decision. Here, we focus on new developments in UPR signaling mechanisms, in the interconnectivity among the signaling pathways that make up the UPR in higher eukaryotes, and in the coordination between the UPR and other fundamental cellular processes

BiP Binding to the ER-Stress Sensor Ire1 Tunes the Homeostatic Behavior of the Unfolded Protein Response

Computational modeling and experimentation in the unfolded protein response reveals a role for the ER-resident chaperone protein BiP in fine-tuning the system's response dynamics

Logistics of community smallpox control through contact tracing and ring vaccination: a stochastic network model

BACKGROUND: Previous smallpox ring vaccination models based on contact tracing over a network suggest that ring vaccination would be effective, but have not explicitly included response logistics and limited numbers of vaccinators. METHODS: We developed a continuous-time stochastic simulation of smallpox transmission, including network structure, post-exposure vaccination, vaccination of contacts of contacts, limited response capacity, heterogeneity in symptoms and infectiousness, vaccination prior to the discontinuation of routine vaccination, more rapid diagnosis due to public awareness, surveillance of asymptomatic contacts, and isolation of cases. RESULTS: We found that even in cases of very rapidly spreading smallpox, ring vaccination (when coupled with surveillance) is sufficient in most cases to eliminate smallpox quickly, assuming that 95% of household contacts are traced, 80% of workplace or social contacts are traced, and no casual contacts are traced, and that in most cases the ability to trace 1–5 individuals per day per index case is sufficient. If smallpox is assumed to be transmitted very quickly to contacts, it may at times escape containment by ring vaccination, but could be controlled in these circumstances by mass vaccination. CONCLUSIONS: Small introductions of smallpox are likely to be easily contained by ring vaccination, provided contact tracing is feasible. Uncertainties in the nature of bioterrorist smallpox (infectiousness, vaccine efficacy) support continued planning for ring vaccination as well as mass vaccination. If initiated, ring vaccination should be conducted without delays in vaccination, should include contacts of contacts (whenever there is sufficient capacity) and should be accompanied by increased public awareness and surveillance

Effect of the one-child policy on influenza transmission in China: a stochastic transmission model

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Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH

Public health management of antiviral drugs during the 2009 H1N1 influenza pandemic: a survey of local health departments in California

<p>Abstract</p> <p>Background</p> <p>The large-scale deployment of antiviral drugs from the Strategic National Stockpile during the 2009 H1N1 influenza response provides a unique opportunity to study local public health implementation of the medical countermeasure dispensing capability in a prolonged event of national significance. This study aims to describe the range of methods used by local health departments (LHDs) in California to manage antiviral activities and to gain a better understanding of the related challenges experienced by health departments and their community partners.</p> <p>Methods</p> <p>This research employed a mixed-methods approach. First, a multi-disciplinary focus group of pandemic influenza planners from key stakeholder groups in California was convened in order to generate ideas and identify critical themes related to the local implementation of antiviral activities during the H1N1 influenza response. These qualitative data informed the development of a web-based survey, which was distributed to all 61 LHDs in California for the purpose of assessing the experiences of a representative sample of local health agencies in a large region.</p> <p>Results</p> <p>Forty-four LHDs participated in this study, representing 72% of the local public health agencies in California. While most communities dispensed a modest number of publicly purchased antivirals, LHDs nevertheless drew on their previous work and engaged in a number of antiviral activities, including: acquiring, allocating, distributing, dispensing, tracking, developing guidance, and communicating to the public and clinical community. LHDs also identified specific antiviral challenges presented by the H1N1 pandemic, including: reconciling multiple sources and versions of antiviral guidance, determining appropriate uses and recipients of publicly purchased antivirals, and staffing shortages.</p> <p>Conclusions</p> <p>The 2009 H1N1 influenza pandemic presented an unusual opportunity to learn about the role of local public health in the management of antiviral response activities during a real public health emergency. Results of this study offer an important descriptive account of LHD management of publicly purchased antivirals, and provide practitioners, policy makers, and academics with a practice-based assessment of these events. The issues raised and the challenges faced by LHDs should be leveraged to inform public health planning for future pandemics and other emergency events that require medical countermeasure dispensing activities.</p

Targeting of XBP1/HAC1 mRNA to Endoplasmic Reticulum Stress Signaling Centers

The unfolded protein response (UPR) comprises a set of endoplasmic reticulum (ER) to nucleus signaling mechanisms that serve to adjust ER size and folding capacity to the cell needs. The core, most conserved UPR mechanism determines the non-canonical splicing of a unique mRNA encoding the transcription factor Hac1 in yeast and XBP1 in higher eukaryotes. The HAC1/XBP1 splicing is initiated by the ER stress sensor/transducer IRE1. Deficiencies in protein folding at the ER drive the clustering of IRE1 molecules into foci in the plane of the ER membrane and the activation of IRE1 kinase and RNAse cytosolic domains. Then, active IRE1 catalyzes the excision of an intron sequence localized within the HAC1/XBP1 messenger RNA, which is followed by ligation of the resulting exons by the tRNA ligase RTCB. Elimination of the intron from HAC1/XBP1 mRNA provides a translational frameshifting and yields the synthesis of Hac1/XBP1s, a key, potent UPR transcription factor. To warrant HAC1/XBP1 splicing efficiency, specific mechanisms foster the encounter between HAC1/XBP1 mRNA and IRE1 clusters at the ER. Although the IRE1 splicing mechanism is conserved from yeast to mammalian cells, different mechanisms that describe the HAC1/XBP1 mRNA transport to ER have been proposed. In yeast, it have been demonstrated that the recruitment of HAC1 mRNA to ER is mediated by an RNA stem loop element (3¿BE) located on the 3¿UTR of HAC1 mRNA and depends on the IRE1 cluster formation and on a translational repression mechanism imposed to HAC1 mRNA. Otherwise, in mammalian cells, a co-translational model explains the selective association of XBP1 mRNA to ER membranes: Ribosomes translating the unspliced XBP1 mRNA produce a hydrophobic peptide (named HR2) that, as it is synthesized by the ribosome, promotes the association of the ribosome/mRNA/nascent chain ternary complex to the cytosolic surface of the ER. Tethering of XBP1 mRNA to ER membranes facilitates its interaction with active IRE1 and the ensuing splicing. Here, we demonstrate HR2 peptide synthesis is necessary to tether XBP1 mRNA to ER, but it is dispensable for splicing under acute ER stress. In line with this notion, we have identified new determinants needed to sustain splicing in a HR2 translation-independent manner. Altogether, we propose a directional targeting mechanism to deliver XBP1 mRNA to IRE1 foci under stress conditions in mammalian cells. Additionally we deepen on the mechanism described for the HAC1 mRNA recruitment in yeast. We found a sequence on the linker domain of Ire1p that produces is necessary to recruit HAC1 mRNA. Furthermore, it was confirmed that the 3¿BE participated in targeting steps that precede HAC1 mRNA docking to Ire1p

Targeting of XBP1/HAC1 mRNA to Endoplasmic Reticulum Stress Signaling Centers

The unfolded protein response (UPR) comprises a set of endoplasmic reticulum (ER) to nucleus signaling mechanisms that serve to adjust ER size and folding capacity to the cell needs. The core, most conserved UPR mechanism determines the non-canonical splicing of a unique mRNA encoding the transcription factor Hac1 in yeast and XBP1 in higher eukaryotes. The HAC1/XBP1 splicing is initiated by the ER stress sensor/transducer IRE1. Deficiencies in protein folding at the ER drive the clustering of IRE1 molecules into foci in the plane of the ER membrane and the activation of IRE1 kinase and RNAse cytosolic domains. Then, active IRE1 catalyzes the excision of an intron sequence localized within the HAC1/XBP1 messenger RNA, which is followed by ligation of the resulting exons by the tRNA ligase RTCB. Elimination of the intron from HAC1/XBP1 mRNA provides a translational frameshifting and yields the synthesis of Hac1/XBP1s, a key, potent UPR transcription factor. To warrant HAC1/XBP1 splicing efficiency, specific mechanisms foster the encounter between HAC1/XBP1 mRNA and IRE1 clusters at the ER. Although the IRE1 splicing mechanism is conserved from yeast to mammalian cells, different mechanisms that describe the HAC1/XBP1 mRNA transport to ER have been proposed. In yeast, it have been demonstrated that the recruitment of HAC1 mRNA to ER is mediated by an RNA stem loop element (3¿BE) located on the 3¿UTR of HAC1 mRNA and depends on the IRE1 cluster formation and on a translational repression mechanism imposed to HAC1 mRNA. Otherwise, in mammalian cells, a co-translational model explains the selective association of XBP1 mRNA to ER membranes: Ribosomes translating the unspliced XBP1 mRNA produce a hydrophobic peptide (named HR2) that, as it is synthesized by the ribosome, promotes the association of the ribosome/mRNA/nascent chain ternary complex to the cytosolic surface of the ER. Tethering of XBP1 mRNA to ER membranes facilitates its interaction with active IRE1 and the ensuing splicing. Here, we demonstrate HR2 peptide synthesis is necessary to tether XBP1 mRNA to ER, but it is dispensable for splicing under acute ER stress. In line with this notion, we have identified new determinants needed to sustain splicing in a HR2 translation-independent manner. Altogether, we propose a directional targeting mechanism to deliver XBP1 mRNA to IRE1 foci under stress conditions in mammalian cells. Additionally we deepen on the mechanism described for the HAC1 mRNA recruitment in yeast. We found a sequence on the linker domain of Ire1p that produces is necessary to recruit HAC1 mRNA. Furthermore, it was confirmed that the 3¿BE participated in targeting steps that precede HAC1 mRNA docking to Ire1p

The role and therapeutic potential of the integrated stress response in amyotrophic lateral sclerosis

In amyotrophic lateral sclerosis (ALS) patients, loss of cellular homeostasis within cortical and spinal cord motor neurons triggers the activation of the integrated stress response (ISR), an intracellular signaling pathway that remodels translation and promotes a gene expression program aimed at coping with stress. Beyond its neuroprotective role, under regimes of chronic or excessive stress, ISR can also promote cell/neuronal death. Given the two-edged sword nature of ISR, many experimental attempts have tried to establish the therapeutic potential of ISR enhancement or inhibition in ALS. This review discusses the complex interplay between ISR and disease progression in different models of ALS, as well as the opportunities and limitations of ISR modulation in the hard quest to find an effective therapy for ALS