Role of HDAC6 and VCP in the regulation of the stress response.Implication in IBMPFD myopathy

Lors d'un stress, les cellules activent un mécanisme de défense appelé “la réponse au stress”. Ce mécanisme empêche notamment l'accumulation de protéines mal enroulées grâce à la synthèse des protéines du choc thermique, les HSPs (Heat Shock Proteins),via l'activation du facteur de transcription HSF1 (Heat Shock Factor 1). Les HSPs empêchent l'agrégation des protéines et aident au repliement protéique. Deux partenaires associés à HSF1 ont récemment été identifiés : le chaperon moléculaire VCP (Valosin Containing Protein) et l'histone déacétylase 6 (HDAC6). Notre projet était d'étudier les rôles d'HDAC6 et de VCP dans la réponse au stress thermique. Nous avons mis en évidence un rôle prépondérant du domaine de fixation à l'ubiquitine d'HDAC6 dans la régulation de la durée d'activation d'HSF1 suite à un choc thermique. Lorsque HDAC6 ne peut pas se fixer à l'ubiquitine, VCP favorise une inactivation rapide de HSF1 empêchant la transcription du chaperon HSP25. Ces travaux montrent également que la réponse activée suite à un stress dépend de la nature de celui-ci. En effet, nous avons montré que les mécanismes activés dans la réponse au stress suite à un choc thermique sont différents de ceux activés suite à une inhibition du protéasome. La myopathie à corps d'inclusion associée à la maladie osseuse de Paget et à une démence fronto-temporale, appelée IBMPFD, Inclusion Body Myopathy associated with Paget disease of the bone and Frontotemporal Dementia, est une maladie autosomale dominante rare. La myopathie est la caractéristique clinique la plus commune parmi celles qui sont causées par des mutations de VCP. La perturbation de la fonction de VCP entraîne l'accumulation de protéines poly-ubiquitinées et la formation de corps d'inclusion en partie responsables de la pathogenèse de l'IBMPFD. Nous avons montré que l'activation de la réponse au stress via un choc thermique dans des cellules murines déficientes en VCP mimant le phénotype de l'IBMPFD, entraîne une diminution du taux de cellules ayant des agrégats de protéines poly-ubiquitinées. Nos résultats préliminaires montrent que HSF1 ne serait pas à l'origine de cette diminution des agrégats au contraire de HSP90 et HDAC6 qui interviendraient suite à l'activation de la réponse au stress. Cette stratégie est actuellement en cours de test sur des modèles murins.Under stress, cells activate a defense mechanism named “cellular stress response”. This mechanism prevents especially unfolded proteins accumulation thanks to Heat Shock Proteins (HSPs) synthesis through the activation of Heat Shock Factor 1 (HSF1) transcription factor. HSPs prevent aggregation and help protein refolding. Two partners associated to HSF1, have recently been identified: the molecular chaperone, VCP (Valosin Containing Protein) and the Histone DeACetylase 6 (HDAC6). Our project was to characterize the roles of HDAC6 and VCP in the Heat Shock Response (HSR). We have highlighted a preponderant role for the HDAC6 ubiquitin binding domain in the HSF1 activation time regulation after a heat shock. When HDAC6 can't bind ubiquitin, VCP promotes a rapid HSF1 inactivation preventing HSP25 chaperone transcription. This work also emphasizes a stimulus-dependent stress response. Indeed, we showed that mechanisms activated during the stress response following a heat shock differ from those activated after a proteasome inhibition. Inclusion Body Myopathy, Paget disease of the bone, and Frontotemporal Dementia (IBMPFD) is a rare autosomal dominant disorder. Myopathy is the most common clinical feature of IBMPFD. It is caused by mutations of VCP. Alteration of VCP function leads to the accumulation of poly-ubiquitinated proteins and to the formation of inclusion bodies thought to be responsible, at least in part, for the pathogenesis of IBMPFD. We have shown that activation of the heat shock stress response in mouse cells VCP deficient mimicking IBMPFD phenotype, results in the decrease of cells with ubiquitinated protein aggregates. Our preliminary results show that HSF1 is not responsible for this decrease unlike HSP90 and HDAC6 that seems to intervene following the stress response activation. This strategy is currently tested on mouse models

Role of HDAC6 and VCP in the regulation of the stress response.Implication in IBMPFD myopathy

Lors d'un stress, les cellules activent un mécanisme de défense appelé “la réponse au stress”. Ce mécanisme empêche notamment l'accumulation de protéines mal enroulées grâce à la synthèse des protéines du choc thermique, les HSPs (Heat Shock Proteins),via l'activation du facteur de transcription HSF1 (Heat Shock Factor 1). Les HSPs empêchent l'agrégation des protéines et aident au repliement protéique. Deux partenaires associés à HSF1 ont récemment été identifiés : le chaperon moléculaire VCP (Valosin Containing Protein) et l'histone déacétylase 6 (HDAC6). Notre projet était d'étudier les rôles d'HDAC6 et de VCP dans la réponse au stress thermique. Nous avons mis en évidence un rôle prépondérant du domaine de fixation à l'ubiquitine d'HDAC6 dans la régulation de la durée d'activation d'HSF1 suite à un choc thermique. Lorsque HDAC6 ne peut pas se fixer à l'ubiquitine, VCP favorise une inactivation rapide de HSF1 empêchant la transcription du chaperon HSP25. Ces travaux montrent également que la réponse activée suite à un stress dépend de la nature de celui-ci. En effet, nous avons montré que les mécanismes activés dans la réponse au stress suite à un choc thermique sont différents de ceux activés suite à une inhibition du protéasome. La myopathie à corps d'inclusion associée à la maladie osseuse de Paget et à une démence fronto-temporale, appelée IBMPFD, Inclusion Body Myopathy associated with Paget disease of the bone and Frontotemporal Dementia, est une maladie autosomale dominante rare. La myopathie est la caractéristique clinique la plus commune parmi celles qui sont causées par des mutations de VCP. La perturbation de la fonction de VCP entraîne l'accumulation de protéines poly-ubiquitinées et la formation de corps d'inclusion en partie responsables de la pathogenèse de l'IBMPFD. Nous avons montré que l'activation de la réponse au stress via un choc thermique dans des cellules murines déficientes en VCP mimant le phénotype de l'IBMPFD, entraîne une diminution du taux de cellules ayant des agrégats de protéines poly-ubiquitinées. Nos résultats préliminaires montrent que HSF1 ne serait pas à l'origine de cette diminution des agrégats au contraire de HSP90 et HDAC6 qui interviendraient suite à l'activation de la réponse au stress. Cette stratégie est actuellement en cours de test sur des modèles murins.Under stress, cells activate a defense mechanism named “cellular stress response”. This mechanism prevents especially unfolded proteins accumulation thanks to Heat Shock Proteins (HSPs) synthesis through the activation of Heat Shock Factor 1 (HSF1) transcription factor. HSPs prevent aggregation and help protein refolding. Two partners associated to HSF1, have recently been identified: the molecular chaperone, VCP (Valosin Containing Protein) and the Histone DeACetylase 6 (HDAC6). Our project was to characterize the roles of HDAC6 and VCP in the Heat Shock Response (HSR). We have highlighted a preponderant role for the HDAC6 ubiquitin binding domain in the HSF1 activation time regulation after a heat shock. When HDAC6 can't bind ubiquitin, VCP promotes a rapid HSF1 inactivation preventing HSP25 chaperone transcription. This work also emphasizes a stimulus-dependent stress response. Indeed, we showed that mechanisms activated during the stress response following a heat shock differ from those activated after a proteasome inhibition. Inclusion Body Myopathy, Paget disease of the bone, and Frontotemporal Dementia (IBMPFD) is a rare autosomal dominant disorder. Myopathy is the most common clinical feature of IBMPFD. It is caused by mutations of VCP. Alteration of VCP function leads to the accumulation of poly-ubiquitinated proteins and to the formation of inclusion bodies thought to be responsible, at least in part, for the pathogenesis of IBMPFD. We have shown that activation of the heat shock stress response in mouse cells VCP deficient mimicking IBMPFD phenotype, results in the decrease of cells with ubiquitinated protein aggregates. Our preliminary results show that HSF1 is not responsible for this decrease unlike HSP90 and HDAC6 that seems to intervene following the stress response activation. This strategy is currently tested on mouse models

SUN2 regulates mitotic duration in response to extracellular matrix rigidity

International audienceHow cells adjust their growth to the spatial and mechanical constraints of their surrounding environment is central to many aspects of biology. Here, we examined how extracellular matrix (ECM) rigidity affects cell division. We found that cells divide more rapidly when cultured on rigid substrates. While we observed no effect of ECM rigidity on rounding or postmitotic spreading duration, we found that changes in matrix stiffness impact mitosis progression. We noticed that ECM elasticity up-regulates the expression of the linker of nucleoskeleton and cytoskeleton (LINC) complex component SUN2, which in turn promotes metaphase-to-anaphase transition by acting on mitotic spindle formation, whereas when cells adhere to soft ECM, low levels of SUN2 expression perturb astral microtubule organization and delay the onset of anaphase

Nuclear envelope deformation controls cell cycle progression in response to mechanical force

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Brainhack: Developing a culture of open, inclusive, community-driven neuroscience

Brainhack is an innovative meeting format that promotes scientific collaboration and education in an open, inclusive environment. This NeuroView describes the myriad benefits for participants and the research community and how Brainhacks complement conventional formats to augment scientific progress

The association between macrovascular complications and intensive care admission, invasive mechanical ventilation, and mortality in people with diabetes hospitalized for coronavirus disease-2019 (COVID-19)

International audienceAbstract Background It is not clear whether pre-existing macrovascular complications (ischemic heart disease, stroke or peripheral artery disease) are associated with health outcomes in people with diabetes mellitus hospitalized for COVID-19. Methods We conducted cohort studies of adults with pre-existing diabetes hospitalized for COVID-19 infection in the UK, France, and Spain during the early phase of the pandemic (between March 2020—October 2020). Logistic regression models adjusted for demographic factors and other comorbidities were used to determine associations between previous macrovascular disease and relevant clinical outcomes: mortality, intensive care unit (ICU) admission and use of invasive mechanical ventilation (IMV) during the hospitalization. Output from individual logistic regression models for each cohort was combined in a meta-analysis. Results Complete data were available for 4,106 (60.4%) individuals. Of these, 1,652 (40.2%) had any prior macrovascular disease of whom 28.5% of patients died. Mortality was higher for people with compared to those without previous macrovascular disease (37.7% vs 22.4%). The combined crude odds ratio (OR) for previous macrovascular disease and mortality for all four cohorts was 2.12 (95% CI 1.83–2.45 with an I 2 of 60%, reduced after adjustments for age, sex, type of diabetes, hypertension, microvascular disease, ethnicity, and BMI to adjusted OR 1.53 [95% CI 1.29–1.81]) for the three cohorts. Further analysis revealed that ischemic heart disease and cerebrovascular disease were the main contributors of adverse outcomes. However, proportions of people admitted to ICU (adjOR 0.48 [95% CI 0.31–0.75], I 2 60%) and the use of IMV during hospitalization (adjOR 0.52 [95% CI 0.40–0.68], I 2 37%) were significantly lower for people with previous macrovascular disease. Conclusions This large multinational study of people with diabetes mellitus hospitalized for COVID-19 demonstrates that previous macrovascular disease is associated with higher mortality and lower proportions admitted to ICU and treated with IMV during hospitalization suggesting selective admission criteria. Our findings highlight the importance correctly assess the prognosis and intensive monitoring in this high-risk group of patients and emphasize the need to design specific public health programs aimed to prevent SARS-CoV-2 infection in this subgroup

Type 1 Diabetes in People Hospitalized for COVID-19: New Insights From the CORONADO Study

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Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old