Volume 2 (2018)
Cover: This month in Cell Stress: Kinase signaling in the innate immune system. Fluorescence microscopic depiction of immune cell responses within the CNS upon chronic pain. Images by Centre for Nanoscale BioPhotonics (CNBP) licensed under the CC BY 2.0 license. Image modified by Cell Stress. The cover is published under the CC BY 4.0 license.
Mitochondrial stress management: a dynamic journey
Miriam Valera-Alberni1,2 and Carles Canto1
Mitochondria undergo continuous challenges in the course of their life, from their generation to their degradation. These challenges include the management of reactive oxygen species, the proper assembly of mitochondrial respiratory complexes and the need to balance potential mutations in the mitochondrial DNA. The detection of damage and the ability to keep it under control is critical to fine-tune mitochondrial function to the organismal energy needs. In this review, we will analyze the multiple mechanisms that safeguard mitochondrial function in light of in crescendo damage. This sequence of events will include initial defense against excessive reactive oxygen species production, compensation mechanisms by the unfolded protein response (UPRmt), mitochondrial dynamics and elimination by mitophagy.
Therapeutic anti-tumor immunity directed against neo-epitopes by intratumor delivery of mRNA encoding MLKL
Lien Van Hoecke1,2 and Xavier Saelens1,2,3
We have developed a potentially generic treatment method to induce tumor antigen-specific cellular immunity based on the transient intra-tumor expression of the necroptosis-inducing factor MLKL (Figure 1). Importantly, we have
Base editors: a powerful tool for generating animal models of human diseases
Zongyang Lu1,2 and Xingxu Huang1,3
BASE EDITORS: A NOVEL GENOME ENGINEERING TOOL Genetically engineered mouse models of human diseases have long been used in understanding the underlying mechanisms of the clinically relevant genetic disorders. In
Unweaving the role of nuclear Lamins in neural circuit integrity
Samantha L. Deal1 and Shinya Yamamoto1,2,3,4
Structural integrity of the nuclear membrane is essential for the homeostasis of eukaryotic cells. Critical components of this process are Lamins or type-V intermediate filament proteins that form a meshwork
Red blood cell extracellular vesicles as robust carriers of RNA-based therapeutics
Chanh Tin Pham1, Xin Zhang1, Austin Lam1, Minh TN Le1
The emerging RNA-based therapeutics are renowned for a wide array of druggable targets, which are difficult to achieve by conventional therapies, with high specificity and great versatility. RNA-based drugs function
New insights into the role of soluble E-cadherin in tumor angiogenesis
Maggie K.S. Tang1, Philip P. Ip2 and Alice S.T. Wong1
Ovarian cancer, the leading cause of death among all gynecological malignancies, is a highly aggressive disease with a propensity for metastasis. Due to the discreet anatomical location, by the time
Neuronal Lamin regulates motor circuit integrity and controls motor function and lifespan
Lisa J. Oyston1,2,3, Yong Qi Lin1, Thang M. Khuong1, Qiao-Ping Wang1, Man Tat Lau1, Teleri Clark1 and G. Gregory Neely1
Neuronal aging involves a progressive decline in cognitive abilities and loss of motor function. Mutations in human Lamin genes (LMNA, LMNB1, LMNB2) lead to a wide-range of diseases including muscular dystrophy, peripheral neuropathy and progeria. Here we investigate the role of neuronal Lamin in regulating age-related phenotypes. Neuronal targeting of Lamin led to shortened lifespan, progressive impairment of motor function and loss of dopaminergic (DA) neurons within the protocerebral anterior medial (PAM) cluster in the Drosophila melanogaster brain. Loss of neuronal Lamin caused an age-related decline in neural physiology, with slower neurotransmission and increased chance of motor circuit failure with age. Unexpectedly, Lamin-dependent decline in motor function was specific for the chemical synapses of the dorsal longitudinal muscle (DLM). Together (...)
Full antagonist of the IL-7 receptor suppresses chronic inflammation in non-human primate models by controlling antigen-specific memory T cells
Lyssia Belarif1, Bernard Vanhove1 and Nicolas Poirier1
Targeting proinflammatory cytokines such as TNFα, IL-1, IL-6, is clinically beneficial in several immune-mediated inflammatory diseases (IMID). However, these cytokines are downstream mediators of immune responses that show poor impact
TRIM16 employs NRF2, ubiquitin system and aggrephagy for safe disposal of stress-induced misfolded proteins
Kautilya Kumar Jena1,2, Subhash Mehto1, Srinivasa Prasad Kolapalli1, Parej Nath1, Swati Chauhan1 and Santosh Chauhan1
We found that under oxidative or proteotoxic stress conditions, the TRIM16 is required for biogenesis of protein aggregates from misfolded proteins. In our attempt to investigate the mechanism by which
Systemic signalling and local effectors in developmental stability, body symmetry, and size
Sergio Juarez-Carreño1, Javier Morante1 and Maria Dominguez1
Symmetric growth and the origins of fluctuating asymmetry are unresolved phenomena of biology. Small, and sometimes noticeable, deviations from perfect bilateral symmetry reflect the vulnerability of development to perturbations. The degree of asymmetry is related to the magnitude of the perturbations and the ability of an individual to cope with them. As the left and right sides of an individual were presumed to be genetically identical, deviations of symmetry were traditionally attributed to non-genetic effects such as environmental and developmental noise. In this review, we draw attention to other possible sources of variability, especially to somatic mutations and transposons. Mutations are a major source of phenotypic variability and recent genomic data have highlighted somatic mutations as ubiquitous, even in phenotypically normal individuals. We discuss the importance of factors that are responsible for buffering and stabilizing the genome (...)
Making the final cut: pathogenic amyloid-β peptide generation by γ-secretase
Harald Steiner1,2, Akio Fukumori3, Shinji Tagami4 and Masayasu Okochi4
Alzheimer´s disease (AD) is a devastating neurodegenerative disease of the elderly population. Genetic evidence strongly suggests that aberrant generation and/or clearance of the neurotoxic amyloid-β peptide (Aβ) is triggering the disease. Aβ is generated from the amyloid precursor protein (APP) by the sequential cleavages of β- and γ-secretase. The latter cleavage by γ-secretase, a unique and fascinating four-component protease complex, occurs in the APP transmembrane domain thereby releasing Aβ species of 37-43 amino acids in length including the longer, highly pathogenic peptides Aβ42 and Aβ43. The lack of a precise understanding of Aβ generation as well as of the functions of other γ-secretase substrates has been one factor underlying the disappointing failure of γ-secretase inhibitors in clinical trials, but on the other side also been a major driving force for structural and in depth mechanistic studies on this key AD drug target in the past few years. Here we (...)
Mechanisms and therapeutic significance of autophagy modulation by antipsychotic drugs
Ljubica Vucicevic1, Maja Misirkic-Marjanovic1, Ljubica Harhaji-Trajkovic1, Nadja Maric2 and Vladimir Trajkovic3
INTRODUCTION The term autophagy (‘self-eating’ in Greek) refers to a group of evolutionarily conserved homeostatic mechanisms employed by eukaryotic cells to eliminate aged, unused, and damaged cytoplasmic components through lysosomal
Full antagonist of the IL-7 receptor suppresses chronic inflammation in non-human primate models by controlling antigen-specific memory T cells
Lyssia Belarif1, Bernard Vanhove1 and Nicolas Poirier1
Targeting proinflammatory cytokines such as TNFα, IL-1, IL-6, is clinically beneficial in several immune-mediated inflammatory diseases (IMID). However, these cytokines are downstream mediators of immune responses that show poor impact
TRIM16 employs NRF2, ubiquitin system and aggrephagy for safe disposal of stress-induced misfolded proteins
Kautilya Kumar Jena1,2, Subhash Mehto1, Srinivasa Prasad Kolapalli1, Parej Nath1, Swati Chauhan1 and Santosh Chauhan1
We found that under oxidative or proteotoxic stress conditions, the TRIM16 is required for biogenesis of protein aggregates from misfolded proteins. In our attempt to investigate the mechanism by which
Systemic signalling and local effectors in developmental stability, body symmetry, and size
Sergio Juarez-Carreño1, Javier Morante1 and Maria Dominguez1
Symmetric growth and the origins of fluctuating asymmetry are unresolved phenomena of biology. Small, and sometimes noticeable, deviations from perfect bilateral symmetry reflect the vulnerability of development to perturbations. The degree of asymmetry is related to the magnitude of the perturbations and the ability of an individual to cope with them. As the left and right sides of an individual were presumed to be genetically identical, deviations of symmetry were traditionally attributed to non-genetic effects such as environmental and developmental noise. In this review, we draw attention to other possible sources of variability, especially to somatic mutations and transposons. Mutations are a major source of phenotypic variability and recent genomic data have highlighted somatic mutations as ubiquitous, even in phenotypically normal individuals. We discuss the importance of factors that are responsible for buffering and stabilizing the genome (...)
Making the final cut: pathogenic amyloid-β peptide generation by γ-secretase
Harald Steiner1,2, Akio Fukumori3, Shinji Tagami4 and Masayasu Okochi4
Alzheimer´s disease (AD) is a devastating neurodegenerative disease of the elderly population. Genetic evidence strongly suggests that aberrant generation and/or clearance of the neurotoxic amyloid-β peptide (Aβ) is triggering the disease. Aβ is generated from the amyloid precursor protein (APP) by the sequential cleavages of β- and γ-secretase. The latter cleavage by γ-secretase, a unique and fascinating four-component protease complex, occurs in the APP transmembrane domain thereby releasing Aβ species of 37-43 amino acids in length including the longer, highly pathogenic peptides Aβ42 and Aβ43. The lack of a precise understanding of Aβ generation as well as of the functions of other γ-secretase substrates has been one factor underlying the disappointing failure of γ-secretase inhibitors in clinical trials, but on the other side also been a major driving force for structural and in depth mechanistic studies on this key AD drug target in the past few years. Here we (...)
Mechanisms and therapeutic significance of autophagy modulation by antipsychotic drugs
Ljubica Vucicevic1, Maja Misirkic-Marjanovic1, Ljubica Harhaji-Trajkovic1, Nadja Maric2 and Vladimir Trajkovic3
INTRODUCTION The term autophagy (‘self-eating’ in Greek) refers to a group of evolutionarily conserved homeostatic mechanisms employed by eukaryotic cells to eliminate aged, unused, and damaged cytoplasmic components through lysosomal
p53 and energy balance: meeting hypothalamic AgRP neurons
Omar Al-Massadi1,2,#, Mar Quiñones1,2,#, Ruben Nogueiras1,2
Cancer cells undergo profound metabolic changes to cope with the high energy demand for cell growth and division. Given the importance of this metabolic reprogramming in tumor development, it seems
Mitochondrial stress management: a dynamic journey
Miriam Valera-Alberni1,2 and Carles Canto1
Mitochondria undergo continuous challenges in the course of their life, from their generation to their degradation. These challenges include the management of reactive oxygen species, the proper assembly of mitochondrial respiratory complexes and the need to balance potential mutations in the mitochondrial DNA. The detection of damage and the ability to keep it under control is critical to fine-tune mitochondrial function to the organismal energy needs. In this review, we will analyze the multiple mechanisms that safeguard mitochondrial function in light of in crescendo damage. This sequence of events will include initial defense against excessive reactive oxygen species production, compensation mechanisms by the unfolded protein response (UPRmt), mitochondrial dynamics and elimination by mitophagy.
Base editors: a powerful tool for generating animal models of human diseases
Zongyang Lu1,2 and Xingxu Huang1,3
BASE EDITORS: A NOVEL GENOME ENGINEERING TOOL Genetically engineered mouse models of human diseases have long been used in understanding the underlying mechanisms of the clinically relevant genetic disorders. In
Unweaving the role of nuclear Lamins in neural circuit integrity
Samantha L. Deal1 and Shinya Yamamoto1,2,3,4
Structural integrity of the nuclear membrane is essential for the homeostasis of eukaryotic cells. Critical components of this process are Lamins or type-V intermediate filament proteins that form a meshwork
Alzheimer’s disease: amyloid-based pathogenesis and potential therapies
Yixiu Zhou1, Yuhui Sun2, Quan-Hong Ma2 and Yaobo Liu2
INTRODUCTION Alzheimer’s disease (AD) is one of the most prevalent forms of dementia; in 2015, for example, AD affected ~46.8 million people worldwide. It is estimated that this number will
Membrane closure in stress induced-autophagosome formation
Eiji Morita1
Autophagy (macroautophagy) is a bulk degradation system that sequesters cytoplasmic components by generating double-layered isolation membranes and delivering these isolated contents to the lysosomes [cite]10.1146/annurev-cellbio-092910-154005[/cite]. Though this pathway was originally
Centriolar satellites prevent uncontrolled degradation of centrosome proteins: a speculative review
Nicolas Lecland1 and Andreas Merdes1
INTRODUCTION Centrosomes are cytoplasmic structures that serve as primary microtubule organizing centers in a large variety of animal cells. They consist of a pair of cylindrically shaped centrioles, surrounded by
Novel role of the SIRT4-OPA1 axis in mitochondrial quality control
Alexander Lang1 and Roland P. Piekorz1
Aging is defined by various molecular and cellular hallmarks, among them stem cell exhaustion, genomic instability, altered proteostasis, cellular senescence, and mitochondrial dysfunction [cite]10.1016/j.cell.2013.05.039[/cite]. Mitochondrial defects are considered major drivers