RESUMEN
We developed JMS-053, a potent inhibitor of the dual specificity phosphatase PTP4A3 that is potentially suitable for cancer therapy. Due to the emerging role of the unfolded protein response (UPR) in cancer pathology, we sought to identify derivatives that combine PTP4A3 inhibition with induction of endoplasmatic reticulum (ER) stress, with the goal to generate more potent anticancer agents. We have now generated bifunctional analogs that link the JMS-053 pharmacophore to an adamantyl moiety and act in concert with the phosphatase inhibitor to induce ER stress and cell death. The most potent compound in this series, 7a, demonstrated a ca. 5-fold increase in cytotoxicity in a breast cancer cell line and strong activation of UPR and ER stress response genes in spite of a ca. 13-fold decrease in PTP4A3 inhibition. These results demonstrate that the combination of phosphatase inhibition with UPR/ER-stress upregulation potentiates efficacy.
Asunto(s)
Antineoplásicos/farmacología , Retículo Endoplásmico/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Iminas/farmacología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Piridinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Femenino , Humanos , Iminas/síntesis química , Iminas/química , Estructura Molecular , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Fosfatasas/metabolismo , Piridinas/síntesis química , Piridinas/química , Relación Estructura-ActividadRESUMEN
To warrant the quality of the secretory proteome, stringent control systems operate at the endoplasmic reticulum (ER)-Golgi interface, preventing the release of nonnative products. Incompletely assembled oligomeric proteins that are deemed correctly folded must rely on additional quality control mechanisms dedicated to proper assembly. Here we unveil how ERp44 cycles between cisGolgi and ER in a pH-regulated manner, patrolling assembly of disulfide-linked oligomers such as IgM and adiponectin. At neutral, ER-equivalent pH, the ERp44 carboxy-terminal tail occludes the substrate-binding site. At the lower pH of the cisGolgi, conformational rearrangements of this peptide, likely involving protonation of ERp44's active cysteine, simultaneously unmask the substrate binding site and -RDEL motif, allowing capture of orphan secretory protein subunits and ER retrieval via KDEL receptors. The ERp44 assembly control cycle couples secretion fidelity and efficiency downstream of the calnexin/calreticulin and BiP-dependent quality control cycles.
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Proteínas de la Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Multimerización de Proteína , Secuencias de Aminoácidos , Sustitución de Aminoácidos , Dominio Catalítico , Ciclo Celular , Retículo Endoplásmico/metabolismo , Aparato de Golgi/metabolismo , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Glicoproteínas de Membrana/metabolismo , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Modelos Moleculares , Chaperonas Moleculares/química , Chaperonas Moleculares/genética , Mutagénesis Sitio-Dirigida , Oxidorreductasas/metabolismo , Transporte de Proteínas , Vías SecretorasRESUMEN
Cancer cells thrive when challenged with proteotoxic stress by inducing components of the protein folding, proteasome, autophagy and unfolded protein response (UPR) pathways. Consequently, specific molecular chaperones have been validated as targets for anti-cancer therapies. For example, inhibition of Hsp70 family proteins (hereafter Hsp70) in rhabdomyosarcoma triggers UPR induction and apoptosis. To define how these cancer cells respond to compromised proteostasis, we compared rhabdomyosarcoma cells that were sensitive (RMS13) or resistant (RMS13-R) to the Hsp70 inhibitor MAL3-101. We discovered that endoplasmic reticulum-associated degradation (ERAD) and autophagy were activated in RMS13-R cells, suggesting that resistant cells overcome Hsp70 ablation by increasing misfolded protein degradation. Indeed, RMS13-R cells degraded ERAD substrates more rapidly than RMS cells and induced the autophagy pathway. Surprisingly, inhibition of the proteasome or ERAD had no effect on RMS13-R cell survival, but silencing of select autophagy components or treatment with autophagy inhibitors restored MAL3-101 sensitivity and led to apoptosis. These data indicate a route through which cancer cells overcome a chaperone-based therapy, define how cells can adapt to Hsp70 inhibition, and demonstrate the value of combined chaperone and autophagy-based therapies.This article has an associated First Person interview with the first author of the paper.
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Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Proteostasis , Rabdomiosarcoma/fisiopatología , Apoptosis , Autofagia , Línea Celular Tumoral , Degradación Asociada con el Retículo Endoplásmico , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Humanos , Complejo de la Endopetidasa Proteasomal/metabolismo , Rabdomiosarcoma/genética , Rabdomiosarcoma/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Respuesta de Proteína DesplegadaRESUMEN
The hippocampus (HP), a medial cortical structure, is subdivided into a distinct dorsal (septal) and ventral (temporal) portion, which is separated by an intermediate region lying on a longitudinal curvature. While the dorsal portion is more dedicated to spatial navigation and memory, the most ventral part processes emotional information. Genetic factors expressed in gradient during development seem to control the size and correct positioning of the HP along its longitudinal axis; however, their roles in regulating differential growth and in supporting its anatomical and functional dissociation remain unexplored. Here, we challenge the in vivo function of the nuclear receptor COUP-TFI (chicken ovalbumin upstream promoter transcription factor 1) in controlling the hippocampal, anatomical, and functional properties along its longitudinal axis. Loss of cortical COUP-TFI function results in a dysmorphic HP with altered shape, volume, and connectivity, particularly in its dorsal and intermediate regions. Notably, topographic inputs from the entorhinal cortex are strongly impaired in the dorsal portion of COUP-TFI mutants. These severe morphological changes are associated with selective spatial learning and memory impairment. These findings identify a novel transcriptional regulator required in the functional organization along the hippocampal septo-temporal axis supporting a genetic basis of the hippocampal volumetric growth with its final shape, circuit, and type of memory function.
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Factor de Transcripción COUP I/genética , Regulación de la Expresión Génica/fisiología , Hipocampo/metabolismo , Animales , Ratones Transgénicos , Regiones Promotoras Genéticas/genética , Transducción de Señal/fisiologíaRESUMEN
The efficient production, folding, and secretion of proteins is critical for cancer cell survival. However, cancer cells thrive under stress conditions that damage proteins, so many cancer cells overexpress molecular chaperones that facilitate protein folding and target misfolded proteins for degradation via the ubiquitin-proteasome or autophagy pathway. Stress response pathway induction is also important for cancer cell survival. Indeed, validated targets for anti-cancer treatments include molecular chaperones, components of the unfolded protein response, the ubiquitin-proteasome system, and autophagy. We will focus on links between breast cancer and these processes, as well as the development of drug resistance, relapse, and treatment.
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Autofagia , Neoplasias de la Mama/genética , Chaperonas Moleculares/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Procesamiento Proteico-Postraduccional , Ubiquitina/metabolismo , Femenino , Humanos , Pliegue de Proteína , Respuesta de Proteína DesplegadaRESUMEN
N-acetyl-l-cysteine (NAC) exhibits protective properties in brain injury models and has undergone a number of clinical trials. Most studies of NAC have focused on neurons. However, neuroprotection may be complemented by the protection of astrocytes because healthier astrocytes can better support the viability of neurons. Here, we show that NAC can protect astrocytes against protein misfolding stress (proteotoxicity), the hallmark of neurodegenerative disorders. Although NAC is thought to be a glutathione precursor, NAC protected primary astrocytes from the toxicity of the proteasome inhibitor MG132 without eliciting any increase in glutathione. Furthermore, glutathione depletion failed to attenuate the protective effects of NAC. MG132 elicited a robust increase in the folding chaperone heat shock protein 70 (Hsp70), and NAC mitigated this effect. Nevertheless, three independent inhibitors of Hsp70 function ablated the protective effects of NAC, suggesting that NAC may help preserve Hsp70 chaperone activity and improve protein quality control without need for Hsp70 induction. Consistent with this view, NAC abolished an increase in ubiquitinated proteins in MG132-treated astrocytes. However, NAC did not affect the loss of proteasome activity in response to MG132, demonstrating that it boosted protein homeostasis and cell viability without directly interfering with the efficacy of this proteasome inhibitor. The thiol-containing molecules l-cysteine and d-cysteine both mimicked the protective effects of NAC, whereas the thiol-lacking molecule N-acetyl-S-methyl-l-cysteine failed to exert protection or blunt the rise in ubiquitinated proteins. Collectively, these findings suggest that the thiol group in NAC is required for its effects on glial viability and protein quality control.
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Acetilcisteína/farmacología , Astrocitos/efectos de los fármacos , Citoprotección/efectos de los fármacos , Glutatión , Pliegue de Proteína/efectos de los fármacos , Animales , Astrocitos/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Citoprotección/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP70 de Choque Térmico/fisiología , Leupeptinas/toxicidad , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
ERp44 is a pH-regulated chaperone of the secretory pathway. In the acidic milieu of the Golgi, its C-terminal tail changes conformation, simultaneously exposing the substrate-binding site for cargo capture and the RDEL motif for ER retrieval through interactions with cognate receptors. Protonation of cysteine 29 in the active site allows tail movements in vitro and in vivo. Here, we show that conserved histidine residues in the C-terminal tail also regulate ERp44 in vivo. Mutants lacking these histidine residues retain substrates more efficiently. Surprisingly, they are also O-glycosylated and partially secreted. Co-expression of client proteins prevents secretion of the histidine mutants, forcing tail opening and RDEL accessibility. Client-induced RDEL exposure allows retrieval of proteins from distinct stations along the secretory pathway, as indicated by the changes in O-glycosylation patterns upon overexpression of different partners. The ensuing gradients might help to optimize folding and assembly of different cargoes. Endogenous ERp44 is O-glycosylated and secreted by human primary endometrial cells, suggesting possible pathophysiological roles of these processes.
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Proteínas Portadoras/metabolismo , Retículo Endoplásmico/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Humanos , Chaperonas Moleculares/genética , Control de Calidad , Vías SecretorasRESUMEN
Genetic variations in catechol-O-methyltransferase (COMT) that modulate cortical dopamine have been associated with pleiotropic behavioral effects in humans and mice. Recent data suggest that some of these effects may vary among sexes. However, the specific brain substrates underlying COMT sexual dimorphisms remain unknown. Here, we report that genetically driven reduction in COMT enzyme activity increased cortical thickness in the prefrontal cortex (PFC) and postero-parieto-temporal cortex of male, but not female adult mice and humans. Dichotomous changes in PFC cytoarchitecture were also observed: reduced COMT increased a measure of neuronal density in males, while reducing it in female mice. Consistent with the neuroanatomical findings, COMT-dependent sex-specific morphological brain changes were paralleled by divergent effects on PFC-dependent working memory in both mice and humans. These findings emphasize a specific sex-gene interaction that can modulate brain morphological substrates with influence on behavioral outcomes in healthy subjects and, potentially, in neuropsychiatric populations.
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Catecol O-Metiltransferasa/genética , Corteza Cerebral/anatomía & histología , Memoria a Corto Plazo/fisiología , Caracteres Sexuales , Adolescente , Adulto , Análisis de Varianza , Animales , Aprendizaje por Asociación/fisiología , Mapeo Encefálico , Catecol O-Metiltransferasa/deficiencia , Corteza Cerebral/citología , Femenino , Genotipo , Proteínas de Homeodominio/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Mutación/genética , Neuronas/metabolismo , Proteínas Nucleares/metabolismo , Fosfopiruvato Hidratasa/metabolismo , Proteínas Represoras/metabolismo , Adulto JovenRESUMEN
Preserving and regulating cellular homeostasis in the light of changing environmental conditions or developmental processes is of pivotal importance for single cellular and multicellular organisms alike. To counteract an imbalance in cellular homeostasis transcriptional programs evolved, called the heat shock response, unfolded protein response, and integrated stress response, that act cell-autonomously in most cells but in multicellular organisms are subjected to cell-nonautonomous regulation. These transcriptional programs downregulate the expression of most genes but increase the expression of heat shock genes, including genes encoding molecular chaperones and proteases, proteins involved in the repair of stress-induced damage to macromolecules and cellular structures. Sixty-one years after the discovery of the heat shock response by Ferruccio Ritossa, many aspects of stress biology are still enigmatic. Recent progress in the understanding of stress responses and molecular chaperones was reported at the 12th International Symposium on Heat Shock Proteins in Biology, Medicine and the Environment in the Old Town Alexandria, VA, USA from 28th to 31st of October 2023.
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Proteínas de Choque Térmico , Medicina , Proteínas de Choque Térmico/metabolismo , Chaperonas Moleculares/metabolismo , Respuesta al Choque Térmico/genética , BiologíaRESUMEN
The dorsal hippocampus is crucial for mammalian spatial memory, but its exact role in item memory is still hotly debated. Recent evidence in humans suggested that the hippocampus might be selectively involved in item short-term memory to deal with an increasing memory load. In this study, we sought to test this hypothesis. To this aim we developed a novel behavioral procedure to study object memory load in mice by progressively increasing the stimulus set size in the spontaneous object recognition task. Using this procedure, we demonstrated that naive mice have a memory span, which is the number of elements they can remember for a short-time interval, of about six objects. Then, we showed that excitotoxic selective lesions of the dorsal hippocampus did not impair novel object discrimination in the condition of low memory load. In contrast, the same lesion impaired novel object discrimination in the high memory load condition, and reduced the object memory span to four objects. These results have important heuristic and clinical implications because they open new perspective toward the understanding of the role of the hippocampus in item memory and in memory span deficits occurring in human pathologies, such as Alzheimer's disease and schizophrenia.
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Hipocampo/fisiología , Reconocimiento en Psicología/fisiología , Animales , Masculino , RatonesRESUMEN
Protein homeostasis (proteostasis) regulates tumor growth and proliferation when cells are exposed to proteotoxic stress, such as during treatment with certain chemotherapeutics. Consequently, cancer cells depend to a greater extent on stress signaling, and require the integrated stress response (ISR), amino acid metabolism, and efficient protein folding and degradation pathways to survive. To define how these interconnected pathways are wired when cancer cells are challenged with proteotoxic stress, we investigated how amino acid abundance influences cell survival when Hsp70, a master proteostasis regulator, is inhibited. We previously demonstrated that cancer cells exposed to a specific Hsp70 inhibitor induce the ISR via the action of two sensors, GCN2 and PERK, in stress-resistant and sensitive cells, respectively. In resistant cells, the induction of GCN2 and autophagy supported resistant cell survival, yet the mechanism by which these events were induced remained unclear. We now report that amino acid availability reconfigures the proteostasis network. Amino acid supplementation, and in particular arginine addition, triggered cancer cell death by blocking autophagy. Consistent with the importance of amino acid availability, which when limited activates GCN2, resistant cancer cells succumbed when challenged with a potentiator for another amino acid sensor, mTORC1, in conjunction with Hsp70 inhibition. IMPLICATIONS: These data position amino acid abundance, GCN2, mTORC1, and autophagy as integrated therapeutic targets whose coordinated modulation regulates the survival of proteotoxic-resistant breast cancer cells.
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Neoplasias de la Mama , Proteostasis , Humanos , Femenino , Estrés Proteotóxico , Supervivencia Celular , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Aminoácidos/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismoRESUMEN
The potential of small molecules to localize within subcellular compartments is rarely explored. To probe this question, we measured the localization of Hsp70 inhibitors using fluorescence microscopy. We found that even closely related analogs had dramatically different distributions, with some residing predominantly in the mitochondria and others in the ER. CRISPRi screens supported this idea, showing that different compounds had distinct chemogenetic interactions with Hsp70s of the ER (HSPA5/BiP) and mitochondria (HSPA9/mortalin) and their co-chaperones. Moreover, localization seemed to determine function, even for molecules with conserved binding sites. Compounds with distinct partitioning have distinct anti-proliferative activity in breast cancer cells compared with anti-viral activity in cellular models of Dengue virus replication, likely because different sets of Hsp70s are required in these processes. These findings highlight the contributions of subcellular partitioning and chemogenetic interactions to small molecule activity, features that are rarely explored during medicinal chemistry campaigns.
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Proteínas HSP70 de Choque Térmico , Chaperonas Moleculares , Sitios de Unión , Chaperón BiP del Retículo Endoplásmico , Proteínas HSP70 de Choque Térmico/metabolismo , Chaperonas Moleculares/metabolismo , Dominios ProteicosRESUMEN
Molecular chaperones, such as Hsp70, prevent proteotoxicity and maintain homeostasis. This is perhaps most evident in cancer cells, which overexpress Hsp70 and thrive even when harboring high levels of misfolded proteins. To define the response to proteotoxic challenges, we examined adaptive responses in breast cancer cells in the presence of an Hsp70 inhibitor. We discovered that the cells bin into distinct classes based on inhibitor sensitivity. Strikingly, the most resistant cells have higher autophagy levels, and autophagy was maximally activated only in resistant cells upon Hsp70 inhibition. In turn, resistance to compromised Hsp70 function required the integrated stress response transducer, GCN2, which is commonly associated with amino acid starvation. In contrast, sensitive cells succumbed to Hsp70 inhibition by activating PERK. These data reveal an unexpected route through which breast cancer cells adapt to proteotoxic insults and position GCN2 and autophagy as complementary mechanisms to ensure survival when proteostasis is compromised.
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Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Autofagia , Neoplasias de la Mama , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Medios de Cultivo/química , Femenino , Técnicas de Silenciamiento del Gen , Proteínas HSP70 de Choque Térmico/genética , Humanos , Proteínas Serina-Treonina Quinasas/genética , Estrés Fisiológico , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismoRESUMEN
The scope of the acid-mediated 3-component synthesis of thiadiazines was investigated. A selective functionalization of the six-membered heterocyclic core structure was accomplished by sequential alkylations, saponifications, and coupling reactions. Several new analogs of a dihydropyrimidinone Hsp70 chaperone agonist, MAL1-271, showed promising activity in a cell based model of Huntington's disease.
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Zinc ions (Zn2+) are imported into the early secretory pathway by Golgi-resident transporters, but their handling and functions are not fully understood. Here, we show that Zn2+ binds with high affinity to the pH-sensitive chaperone ERp44, modulating its localization and ability to retrieve clients like Ero1α and ERAP1 to the endoplasmic reticulum (ER). Silencing the Zn2+ transporters that uptake Zn2+ into the Golgi led to ERp44 dysfunction and increased secretion of Ero1α and ERAP1. High-resolution crystal structures of Zn2+-bound ERp44 reveal that Zn2+ binds to a conserved histidine-cluster. The consequent large displacements of the regulatory C-terminal tail expose the substrate-binding surface and RDEL motif, ensuring client capture and retrieval. ERp44 also forms Zn2+-bridged homodimers, which dissociate upon client binding. Histidine mutations in the Zn2+-binding sites compromise ERp44 activity and localization. Our findings reveal a role of Zn2+ as a key regulator of protein quality control at the ER-Golgi interface.
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Proteínas de la Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Vías Secretoras , Zinc/metabolismo , Aminopeptidasas/metabolismo , Sitios de Unión/genética , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Cristalografía por Rayos X , Retículo Endoplásmico/metabolismo , Aparato de Golgi/metabolismo , Células HeLa , Células Hep G2 , Humanos , Glicoproteínas de Membrana/metabolismo , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Antígenos de Histocompatibilidad Menor/metabolismo , Chaperonas Moleculares/química , Chaperonas Moleculares/genética , Oxidorreductasas/metabolismo , Unión Proteica , Conformación Proteica , Multimerización de Proteína , Control de Calidad , Interferencia de ARN , Zinc/químicaRESUMEN
Antipsychotics are the most widely used medications for the treatment of schizophrenia spectrum disorders. While such drugs generally ameliorate positive symptoms, clinical responses are highly variable in terms of negative symptoms and cognitive impairments. However, predictors of individual responses have been elusive. Here, we report a pharmacogenetic interaction related to a core cognitive dysfunction in patients with schizophrenia. We show that genetic variations reducing dysbindin-1 expression can identify individuals whose executive functions respond better to antipsychotic drugs, both in humans and in mice. Multilevel ex vivo and in vivo analyses in postmortem human brains and genetically modified mice demonstrate that such interaction between antipsychotics and dysbindin-1 is mediated by an imbalance between the short and long isoforms of dopamine D2 receptors, leading to enhanced presynaptic D2 function within the prefrontal cortex. These findings reveal one of the pharmacodynamic mechanisms underlying individual cognitive response to treatment in patients with schizophrenia, suggesting a potential approach for improving the use of antipsychotic drugs.
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Antipsicóticos/farmacología , Disbindina/genética , Adolescente , Adulto , Anciano , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cognición/efectos de los fármacos , Cognición/fisiología , Disbindina/deficiencia , Disbindina/metabolismo , Función Ejecutiva/efectos de los fármacos , Función Ejecutiva/fisiología , Variación Genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Receptores de Dopamina D2/metabolismo , Risperidona/farmacología , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Esquizofrenia/metabolismo , Psicología del Esquizofrénico , Adulto JovenRESUMEN
In the original version of this Article, references in the Methods section incorrectly referred to references in the Supplementary References section. The relevant references (now numbered 20, 27, 42, 47, 69-80) have been removed from the Supplementary References section of the Supplementary Information file and added to the References section of the main manuscript, in both the PDF and HTML versions of the Article.
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The hypothalamic neuropeptide oxytocin (OT) is a forefront molecule among neuropeptides due to its pronounced prosocial effects and its potential use in socioemotional deficits that characterize the most prevalent neurodevelopmental and psychiatric disorders (autism spectrum disorders and schizophrenia). The effects of OT have been studied in young and adult subjects (either animals or humans), while the complete lifespan trajectories of OT system development and activity have been far less investigated. In this (mini) review, we will primarily focus on three temporal distinct periods of life-early postnatal period, puberty/adolescence, and elderly. We selected the neonatal period to discuss the role of OT in the switch of GABA action from excitation to inhibition in the first days after birth (in rodents), with potential implications in neurodevelopmental disorders. In the puberty/adolescence period, we consider of particular relevance the OT impact on drug consumption, stress and aggression. Finally, OT could potentially contribute to maintain social capacities of aged people and to ameliorate socially emotional deficits and symptoms of neurodegenerative diseases. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 158-168, 2017.
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Desarrollo Humano/fisiología , Trastornos del Neurodesarrollo/metabolismo , Oxitocina/fisiología , Transducción de Señal/fisiología , Animales , HumanosRESUMEN
In multicellular organisms, some cells are given the task of secreting huge quantities of proteins. To comply with their duty, they generally equip themselves with a highly developed endoplasmic reticulum (ER) and downstream organelles in the secretory pathway. These professional secretors face paramount proteostatic challenges in that they need to couple efficiency and fidelity in their secretory processes. On one hand, stringent quality control (QC) mechanisms operate from the ER onward to check the integrity of the secretome. On the other, the pressure to secrete can be overwhelming, as for instance on antibody-producing cells during infection. Maintaining homeostasis is particularly hard when the products to be released contain disulfide bonds, because oxidative folding entails production of reactive oxygen species. How are redox homeostasis ("redoxtasis") and proteostasis maintained despite the massive fluxes of cargo proteins traversing the pathway? Here we describe recent findings on how ERp44, a multifunctional chaperone of the secretory pathway, can modulate these processes integrating protein QC, redoxtasis, and calcium signaling.
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Homeostasis/fisiología , Inmunoglobulinas/metabolismo , Proteínas de la Membrana/metabolismo , Chaperonas Moleculares/metabolismo , Vías Secretoras , Secuencia de Aminoácidos , Animales , Retículo Endoplásmico/fisiología , Humanos , Inmunoglobulinas/química , Proteínas de la Membrana/química , Chaperonas Moleculares/química , Datos de Secuencia Molecular , Oxidación-Reducción , Pliegue de Proteína , Homología de Secuencia de AminoácidoRESUMEN
Different genetic variations in the catechol-O-methyltransferase (COMT) gene have been indicated to functionally regulate the encoded enzyme. Despite the vast literature on the single nucleotide COMT ValMet polymorphism, the impact of complex haplotypes on cognitive functions has been overlooked. Here we contrasted the effects of complex COMT haplotypes with the ValMet polymorphism on cognitive functions and their interaction with menopause, in healthy subjects and patients with schizophrenia. Healthy adults (N=229) as well as patients with schizophrenia (N=172) underwent a comprehensive cognitive assessment taking into account the menopausal state. Functional COMT variations selectively modulated working memory and executive functions. Strikingly, these effects were present only in adult men but not in women before menopause, in both healthy subjects and patients with schizophrenia. Importantly, the same pattern of COMT-dependent effects present in men reappeared in women after menopause. Thus, functional COMT mutations seem to modulate cognitive functions depending on the hormonal status. These data clarify the importance of taking into account the combined effect of sex, hormonal status and genetics.