In innate immune responses, induction of type-I interferons (IFNs) prevents virus spreading while viral replication is delayed by protein synthesis inhibition. We asked how cells perform these apparently contradictory activities. Using single fibroblast monitoring by flow cytometry and mathematical modeling, we demonstrate that type-I IFN production is linked to cell's ability to enter dsRNA-activated PKR-dependent translational arrest and then overcome this inhibition by decreasing eIF2a phosphorylation through phosphatase 1c cofactor GADD34 (Ppp1r15a) expression. GADD34 expression, shown here to be dependent on the IRF3 transcription factor, is responsible for a biochemical cycle permitting pulse of IFN synthesis to occur in cells undergoing protein synthesis inhibition. Translation arrest is further demonstrated to be key for anti-viral response by acting synergistically with MAVS activation to amplify TBK1 signaling and IFN-b mRNA transcription, while GADD34-dependent protein synthesis recovery contributes to the heterogeneous expression of IFN observed in dsRNA-activated cells.

Protein ubiquitination, a major post-translational modification in eukaryotes, requires an adequate pool of free ubiquitin. Cells maintain this pool by two pathways, both involving deubiquitinases (DUBs): recycling of ubiquitin from ubiquitin conjugates and processing of ubiquitin precursors synthesized de novo. Although many advances have been made in recent years regarding ubiquitin recycling, our knowledge on ubiquitin precursor processing is still limited, and questions such as when are these precursors processed and which DUBs are involved remain largely unanswered. Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. The identification of these DUBs together with their properties suggests that each ubiquitin precursor can be processed in at least two different manners, explaining the robustness of the ubiquitin de novo synthesis pathway.

Immune cells detect specific microbes or damage to tissue integrity in order to initiate efficient immune responses. Abnormal accumulation of proteins in the endoplasmic reticulum (ER) can be seen as a sign of cellular malfunction and stress that triggers a collection of conserved emergency rescue programs. These different signaling cascades, which favor ER proteostasis and promote cell survival, are collectively known as the unfolded protein response (UPR). In recent years, a synergy between the UPR and inflammatory cytokine production has been unraveled, with different branches of the UPR entering in a cross‐talk with specialized microbe sensing pathways, which turns on or amplify inflammatory cytokines production. Complementary to this synergetic activity, UPR induction alone, can itself be seen as a danger signal, and triggers directly or indirectly inflammation in different cellular and pathological models, this independently of the presence of pathogens. Here, we discuss recent advances on the nature of these cross‐talks and how innate immunity, metabolism dysregulation, and ER‐signaling pathways intersect in specialized immune cells, such as dendritic cells (DCs), and contribute to the pathogenesis of inflammatory diseases.

Objective: To estimate the time of decision (TD) to look for medical care and the time of arrival (TA) at the health service for men (M) and women (W) suffering from acute myocardial infarction and to analyze the influence of the interpretation of pain and pain resistance behaviors during these times. Methods: This is an exploratory research, performed at the university hospital in Salvador/Bahia. 43 W and 54 M were interviewed. To study the dependence among sociodemographic and gender variables, the Fisher Exact Test was used. To analyze times, a geometric mean (GM) was used. In order to verify the association between the GM of TD and TA and the judgment of pain, and between the GM of TD and TA and the behavior of resistance to pain, as well as to test the time of interaction between the gender variable and other variables of interest, the robust regression model was used. The statistical significance adopted was 5%. Results: The GM of the TD for M was 1.13 h; for W, 0.74 h. The GM of the TA was 1.74 h for M and 1.47 h for W. Those who did not recognize the symptoms of AMI and presented behavior of resistance to pain had higher TD and TA, being the associations significant. Gender did not change the associations of interest. Conclusion:The findings demonstrate the importance of health education aiming at the benefits of early treatment.

Endoplasmic reticulum (ER) stress triggers or amplifies inflammatory signals and cytokine production in immune cells. Upon the resolution of ER stress, the inducible phosphatase 1 cofactor GADD34 promotes the dephosphorylation of the initiation factor eIF2α, thereby enabling protein translation to resume. Several aminoguanidine compounds, such as guanabenz, perturb the eIF2α phosphorylation-dephosphorylation cycle and protect different cell or tissue types from protein misfolding and degeneration. We investigated how pharmacological interference with the eIF2α pathway could be beneficial to treat autoinflammatory diseases dependent on proinflammatory cytokines and type I interferons (IFNs), the production of which is regulated by GADD34 in dendritic cells (DCs). In mouse and human DCs and B cells, guanabenz prevented the activation of Toll-like receptor 9 (TLR9) by CpG oligodeoxynucleotides or DNA-immunoglobulin complexes in endosomes. In vivo, guanabenz protected mice from CpG oligonucleotide-dependent cytokine shock and decreased autoimmune symptom severity in a chemically induced model of systemic lupus erythematosus. However, we found that guanabenz exerted its inhibitory effect independently of GADD34 activity on eIF2α and instead decreased the abundance of CH25H, a cholesterol hydroxylase linked to antiviral immunity. Our results therefore suggest that guanabenz and similar compounds could be used to treat type I IFN-dependent pathologies and that CH25H could be a therapeutic target to control these diseases.

Protein modification with the small ubiquitin-like modifier (SUMO) is a reversible process regulating many central biological pathways. The reversibility of SUMOylation is ensured by SUMO proteases many of which belong to the sentrin/SUMO-specific protease (SENP) family. In recent years, many advances have been made in allocating SENPs to specific biological pathways. However, due to difficulties in obtaining recombinant full-length active SENPs for thorough enzymatic characterization, our knowledge on these proteases is still limited. In this work, we used in vitro synthesized full-length human SENPs to perform a side-by-side comparison of their activities and substrate specificities. ProSUMO1/2/3, RanGAP1-SUMO1/2/3 and polySUMO2/3 chains were used as substrates in these analyses. We found that SENP1 is by far the most versatile and active SENP whereas SENP3 stands out as the least active of these enzymes. Finally, a comparison between the activities of full-length SENPs and their catalytic domains suggests that in some cases their non-catalytic regions influence their activity.

Portuguese / English: www.scielo.br/reeusp RESUMO Estudo de corte transversal que avaliou parâmetros clínicos e antropométricos em 100 indivíduos com doença arterial coronária, atendidos em um ambulatório de cardiologia preventiva em um hospital público, em Salvador/BA. Na coleta de dados empregou-se entrevista, avaliação clínica e laboratorial. Os resultados foram analisados em médias e percentuais. Predominou homens, faixa etária <60 anos, raça/cor negra casado(a)s, baixa escolaridade e renda, indivíduos sem ocupação e com diagnóstico de infarto do miocárdio. A maioria relatou hipertensão arterial, dislipidemia, sedentarismo, abandono do tabagismo e da bebida alcoólica. Todas as mulheres e 82% dos homens tinham circunferência abdominal aumentada, 19% glicemia casual >200 mg/ dL, 36% sobrepeso, 28% obesidade, 65% algum estágio de hipertensão arterial, 65% HDL-C baixo e 43% estava com colesterol total alto. Em indivíduos de alto risco cardiovascular e condições socioeconômicas deficitárias constatou-se o descontrole de vários fatores de risco cardiovascular, demandando práticas de cuidar efetivas para o controle da doença. DESCRITORES ABSTRACTThis cross-sectional study evaluated the clinical and anthropometrical parameters of 100 individuals with coronary artery disease, who were assisted at preventive cardiology outpatient clinic at a public hospital in Salvador/BA. Data collection was performed through interviews and both clinical and laboratory evaluations. The results were analyzed as averages and percentages. Most participants were black men, aged <60 years, married, low education level and small income, unemployed and diagnosed with myocardial infarction. Most reported having arterial hypertension, dyslipidemia, a sedentary lifestyle, and had quit smoking and drinking. All women and 82% of the men had an increased abdominal circumference, 19% had causal blood glucose>200 mg/dL, 36% was overweight, 28% were obese, 65% were in soma stage of hypertension, 65% had low HDL-C and 43% had high total cholesterol. It was observed that individuals with high cardiovascular risk and deficient socioeconomic conditions show a lack of control of several cardiovascular risk factors, thus demanding effective health care practices to control the illness.

BackgroundPsoriasis is a chronic dermatosis of unknown etiology with a tendency to relapse after treatment. The disease is frequently linked to psychological stress due to the embarrassment caused by the lesions.ObjectiveTo analyze the stress level presented by psoriasis patients followed at the Dermatology Service of a public hospital in Salvador, Bahia state, Brazil.MethodsA cross-sectional study of a consecutive convenience sample composed of 60 participants. We used Lipp's Stress Symptoms Inventory for Adults to assess stress levels. The questionnaire identifies and classifies physical and psychological symptoms according to three stages of stress: alarming, resistance, and exhaustion. We also collected socio-demographic and clinical data that could be associated with psoriasis.Results85% of the participants presented stress. Lipp's questionnaire results revealed that 48% were in the resistance stage and 37% in the exhaustion stage. Women presented higher levels of stress. Of the total 28 women, 64% were in exhaustion stage, 29% in the resistance stage, and only 7% presented no stress symptoms. Of the total 32 men, 44% were in resistance stage, 34% in exhaustion stage, and 22% presented no stress symptoms. Regarding physical and psychological symptoms, psychological symptomatology was prevalent (55%).ConclusionsBased on the number of patients in exhaustion stage, we can conclude that stress levels of the participants were high regardless the type of psoriasis and treatment duration.