Involvement of the p62/NRF2 signal transduction pathway on erythrophagocytosis

This deposit is composed by the main article plus the supplementary materials of the publication.Erythrophagocytosis, the phagocytic removal of damaged red blood cells (RBC), and subsequent phagolysosome biogenesis are important processes in iron/heme metabolism and homeostasis. Phagolysosome biogenesis implies the interaction of nascent phagosomes with endocytic compartments and also autophagy effectors. Here, we report that besides recruitment of microtubule-associated protein-1-light chain 3 (LC3), additional autophagy machinery such as sequestosome 1 (p62) is also acquired by single-membrane phagosomes at very early stages of the phagocytic process and that its acquisition is very important to the outcome of the process. In bone marrow-derived macrophages (BMDM) silenced for p62, RBC degradation is inhibited. P62, is also required for nuclear translocation and activation of the transcription factor Nuclear factor E2-related Factor 2 (NRF2) during erythrophagocytosis. Deletion of the Nrf2 allele reduces p62 expression and compromises RBC degradation. In conclusion, we reveal that erythrophagocytosis relies on an interplay between p62 and NRF2, potentially acting as protective mechanism to maintain reactive oxygen species at basal levels and preserve macrophage homeostasis.Fundação para a Ciência e a Tecnologia grants: (HMSP-ICT/0024/2010, UID/Multi/04462/2013, SFRH/BD/62197/2009, SFRH/BD/90258/2012, SFRH /BD/51877/2012, SFRH/BD/52293/2013, PTDC/SAU-TOX/116627/2010, HMSP-ICT/0022/2010 ); European Union FEDER support: (COMPETE, QREN, PT2020 Partnership Agreement), ERC grant: (ERC-2011-AdG 294709-DAMAGECONTROL).info:eu-repo/semantics/publishedVersio

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Crystal structure of isopenicillin <i>N</i> synthase is the first from a new structural family of enzymes

Penicillin antibiotics are all produced from fermentation-derived penicillins because their chemical synthesis is not commercially viable. The key step in penicillin biosynthesis, in which both the beta-lactam and thiazolidine rings of the nucleus are created, is mediated by isopenicillin N synthase (IPNS), which binds ferrous iron and uses dioxygen as a cosubstrate. In a unique enzymatic step, with no chemical precedent, IPNS catalyses the transfer of four hydrogen atoms from its tripeptide substrate to dioxygen forming, in a single reaction, the complete bicyclic nucleus of the penicillins. We now report the structure of IPNS complexed with manganese, which reveals the active site is unusually buried within a 'jelly-roll' motif and lined by hydrophobic residues, and suggest how this structure permits the process of penicillin formation. Sequence analyses indicate IPNS, 1-aminocyclopropane-1-carboxylic acid oxidase and many of the 2-oxo-acid-dependent oxygenases contain a conserved jelly-roll motif, forming a new structural family of enzymes

Características contextuais de vizinhança e atividade física de lazer: Estudo Pró-Saúde

OBJETIVO Estimar a associação entre variáveis contextuais de vizinhança e prática de atividade física de lazer. MÉTODOS Foram analisados dados de 2.674 participantes adultos de estudo longitudinal no Rio de Janeiro, RJ, em 1999. A atividade física de lazer, avaliada de forma dicotômica, referiu-se às duas semanas prévias à pesquisa. Sexo, idade, renda, escolaridade e situação conjugal foram analisados como variáveis individuais. Características contextuais referentes às vizinhanças (bairros) foram índice de desenvolvimento social, índice de Theil e proporção de área de parques, praças e jardins, categorizadas em quintis. Foram estimadas razões de chances brutas e ajustadas e intervalos de confiança de 95% por meio de regressão logística multinível. RESULTADOS As prevalências de atividade física de lazer foram maiores entre residentes de bairros com maiores índices de desenvolvimento social (entre 32,3% e 55,4%) e proporção de área de parques, praças e jardins (entre 35,8% e 53,1%). Para o índice de desenvolvimento social, quando comparados aos residentes de bairros do primeiro quintil, as razões de chances ajustadas de atividade física de lazer para variáveis individuais foram 1,22 (IC95% 0,93;1,61), 1,44 (IC95% 1,09;1,89), 1,75 (IC95% 1,31;2,34) e 2,25 (IC95% 1,70; 3,00) entre residentes de bairros do segundo, terceiro, quarto e quinto quintis. As razões de chances relativas à proporção de área de parques, praças e jardins foram 0,90 (IC95% 0,69;1,19), 1,41 (IC95% 1,04;1,90), 1,63 (IC95% 1,24;2,14) e 1,05 (IC95% 0,80;1,38) entre residentes de bairros dos segundo, terceiro, quarto e quinto quintis. Após ajuste para as demais variáveis contextuais, somente o índice de desenvolvimento social permaneceu associado à atividade física de lazer, com razões de chances de 1,41 (IC95% 1,02;1,95), 1,54 (IC95% 1,12;2,12); 1,65 (IC95% 1,14;2,39) e 2,13 (IC95% 1,40;3,25) para residentes de bairros dos segundo, terceiro, quarto e quinto quintis. CONCLUSÕES A atividade física de lazer foi mais frequente entre residentes de bairros com maiores índices de desenvolvimento social. Não foram observadas associações com acesso a espaços de lazer e desigualdade de renda