Male sex is one of the determinants of severe coronavirus diseas-e-2019 (COVID-19). We aimed to characterize sex differences in severe outcomes in adults with diabetes hospitalized for COVID-19.
We ...performed a sex-stratified analysis of clinical and biological features and outcomes (i.e. invasive mechanical ventilation (IMV), death, intensive care unit (ICU) admission and home discharge at day 7 (D7) or day 28 (D28)) in 2380 patients with diabetes hospitalized for COVID-19 and included in the nationwide CORONADO observational study (NCT04324736).
The study population was predominantly male (63.5%). After multiple adjustments, female sex was negatively associated with the primary outcome (IMV and/or death, OR: 0.66 (0.49-0.88)), death (OR: 0.49 (0.30-0.79)) and ICU admission (OR: 0.57 (0.43-0.77)) at D7 but only with ICU admission (OR: 0.58 (0.43-0.77)) at D28. Older age and a history of microvascular complications were predictors of death at D28 in both sexes, while chronic obstructive pulmonary disease (COPD) was predictive of death in women only. At admission, C-reactive protein (CRP), aspartate amino transferase (AST) and estimated glomerular filtration rate (eGFR), according to the CKD-EPI formula predicted death in both sexes. Lymphocytopenia was an independent predictor of death in women only, while thrombocytopenia and elevated plasma glucose concentration were predictors of death in men only.
In patients with diabetes admitted for COVID-19, female sex was associated with lower incidence of early severe outcomes, but did not influence the overall in-hospital mortality, suggesting that diabetes mitigates the female protection from COVID-19 severity. Sex-associated biological determinants may be useful to optimize COVID-19 prevention and management in women and men.
Protein phosphatase 2A (PP2A) is a large family of holoenzymes that comprises 1% of total cellular proteins and accounts for the majority of Ser/Thr phosphatase activity in eukaryotic cells. Although ...initially viewed as constitutive housekeeping enzymes, it is now well established that PP2A proteins represent a family of highly and sophistically regulated phosphatases. The past decade, multiple complementary studies have improved our knowledge about structural and functional regulation of PP2A holoenzymes. In this regard, after summarizing major cellular regulation, this review will mainly focus on discussing a particulate biological strategy, used by various viruses, which is based on the targeting of PP2A enzymes by viral proteins in order to specifically deregulate, for their own benefit, cellular pathways of their hosts. The impact of such PP2A targeting for research in human diseases, and in further therapeutic developments, is also discussed.
► The family of PP2A holoenzymes are specific targets for multiple viruses. ► Viruses use PP2A to specifically subvert key survival pathways of their hosts. ► Proteins encoded by DNA/RNA tumor viruses bind PP2A to activate oncogenic pathways. ► PP2A dysfunction is associated to cancer and neurodegeneration. ► The study of PP2A dysfunction is a powerful approach for human therapy.
Human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2 encode auxiliary proteins that play important roles in viral replication, viral latency, and immune escape. The presence of auxiliary ...protein-encoding open reading frames (ORFs) in HTLV-3, the latest HTLV to be discovered, is unknown. Simian T-cell lymphotropic virus type 3 (STLV-3) is almost identical to HTLV-3. Given the lack of HTLV-3-infected cell lines, we took advantage of STLV-3-infected cells and of an STLV-3 molecular clone to search for the presence of auxiliary transcripts. Using reverse transcriptase PCR (RT-PCR), we first uncovered the presence of three unknown viral mRNAs encoding putative proteins of 5, 8, and 9 kDa and confirmed the presence of the previously reported RorfII transcript. The existence of these viral mRNAs was confirmed by using splice site-specific RT-PCR with ex vivo samples. We showed that p5 is distributed throughout the cell and does not colocalize with a specific organelle. The p9 localization is similar to that of HTLV-1 p12 and induced a strong decrease in the calreticulin signal, similarly to HTLV-1 p12. Although p8, RorfII, and Rex-3 share an N-terminal sequence that is predicted to contain a nucleolar localization signal (NoLS), only p8 is found in the nucleolus. The p8 location in the nucleolus is linked to a bipartite NoLS. p8 and, to a lesser extent, p9 repressed viral expression but did not alter Rex-3-dependent mRNA export. Using a transformation assay, we finally showed that none of the STLV-3 auxiliary proteins had the ability to induce colony formation, while both Tax-3 and antisense protein of HTLV-3 (APH-3) promoted cellular transformation. Altogether, these results complete the characterization of the newly described primate T-lymphotropic virus type 3 (PTLV-3).
Together with their simian counterparts, HTLVs form the primate T-lymphotropic viruses. HTLVs arose from interspecies transmission between nonhuman primates and humans. HTLV-1 and HTLV-2 encode auxiliary proteins that play important roles in viral replication, viral latency, and immune escape. The presence of ORFs encoding auxiliary proteins in HTLV-3 or STLV-3 genomes was unknown. Using in silico analyses, ex vivo samples, or in vitro experiments, we have uncovered the presence of 3 previously unknown viral mRNAs encoding putative proteins and confirmed the presence of a previously reported viral transcript. We characterized the intracellular localization of the four proteins. We showed that two of these proteins repress viral expression but that none of them have the ability to induce colony formation. However, both Tax and the antisense protein APH-3 promote cell transformation. Our results allowed us to characterize 4 new retroviral proteins for the first time.
La famille des protéine phosphatases PP2A Godet, Angélique N.; Guergnon, Julien; Galioot, Amandine ...
M.S. Médecine sciences,
12/2011, Letnik:
27, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Les holoenzymes de la famille des protéine phosphatases 2A (PP2A) représentent 1 % des protéines de la cellule eucaryote et constituent la majorité de l’activité sérine/thréonine phosphatase de ces ...cellules. Ces holoenzymes contiennent un noyau dimérique appelé « core », formé d’une sous-unité catalytique (C) et d’une sous-unité structurale (A), auquel peut être associée une sous-unité régulatrice (B) variable. Initialement considérées comme des enzymes constitutivement actives, les PP2A peuvent être régulées par des modifications post-traductionnelles ou par l’induction des sous-unités régulatrices de type B qui en contrôlent l’activité. Lors des deux dernières décennies, des études basées sur l’interaction fonctionnelle de PP2A avec des protéines virales ont permis d’identifier des voies de signalisation critiques pour la biologie des virus et pour l’induction des processus tumoraux. À ce jour, on a déjà identifié une douzaine de virus différents (ADN/ARN et rétrovirus) codant pour des protéines virales associées à des PP2A. Nous analysons dans cette revue une stratégie basée sur l’interaction de protéines virales avec les protéines PP2A qui aboutit à une dérégulation spécifique de certaines voies de signalisation cellulaires. L’impact du ciblage viral des PP2A sur la recherche biomédicale et sur le développement de nouvelles approches thérapeutiques contre le cancer sera aussi discuté.
Protein phosphatase 2A (PP2A) is a large family of holoenzymes that comprises 1% of total cellular proteins and accounts for the majority of Ser/Thr phosphatase activity in eukaryotic cells. PP2A proteins are made of a core dimer, composed of a catalytic (C) subunit and a structural (A) subunit, in association with a third variable regulatory (B) subunit. Although initially considered as a constitutive housekeeping enzyme, PP2A is indeed highly regulated by post-translational modifications of its catalytic subunit or by the identity of a regulatory type B subunit, which determines substrate specificity, subcellular localization and enzymatic activity of a defined holoenzyme. During the two last decades, multiple studies of structural and functional regulation of PP2A holoenzymes by viral proteins led to the identification of critical pathways for both viral biology and tumorigenesis. To date a dozen of different viruses (ADN/ARN or retrovirus) have been identified that encode viral proteins associated to PP2A. In this review, we analyze a biological strategy, used by various viruses based on the targeting of PP2A enzymes by viral proteins, in order to specifically deregulate cellular pathways of their hosts. The impact of such PP2A targeting for biomedical search, and in further therapeutic developments against cancer, will also be discussed.
Protein phosphatase 2A (PP2A) is a large family of holoenzymes that comprises 1% of total cellular proteins and accounts for the majority of Ser/Thr phosphatase activity in eukaryotic cells. PP2A ...proteins are made of a core dimer, composed of a catalytic (C) subunit and a structural (A) subunit, in association with a third variable -regulatory (B) subunit. Although initially considered as a constitutive housekeeping enzyme, PP2A is indeed highly regulated by post-translational modifications of its catalytic subunit or by the identity of a regulatory type B subunit, which determines substrate specificity, subcellular localization and enzymatic activity of a defined holoenzyme. During the two last decades, multiple studies of structural and functional regulation of PP2A holoenzymes by viral proteins led to the identification of critical pathways for both viral biology and tumorigenesis. To date a dozen of different viruses (ADN/ARN or retrovirus) have been identified that encode viral proteins associated to PP2A. In this review, we analyze a biological strategy, used by various viruses based on the targeting of PP2A enzymes by viral proteins, in order to specifically deregulate cellular pathways of their hosts. The impact of such PP2A targeting for biomedical search, and in further therapeutic developments against cancer, will also be discussed.
Protein phosphatase 2A (PP2A) is a large family of holoenzymes that comprises 1% of total cellular proteins and accounts for the majority of Ser/Thr phosphatase activity in eukaryotic cells. PP2A ...proteins are made of a core dimer, composed of a catalytic (C) subunit and a structural (A) subunit, in association with a third variable -regulatory (B) subunit. Although initially considered as a constitutive housekeeping enzyme, PP2A is indeed highly regulated by post-translational modifications of its catalytic subunit or by the identity of a regulatory type B subunit, which determines substrate specificity, subcellular localization and enzymatic activity of a defined holoenzyme. During the two last decades, multiple studies of structural and functional regulation of PP2A holoenzymes by viral proteins led to the identification of critical pathways for both viral biology and tumorigenesis. To date a dozen of different viruses (ADN/ARN or retrovirus) have been identified that encode viral proteins associated to PP2A. In this review, we analyze a biological strategy, used by various viruses based on the targeting of PP2A enzymes by viral proteins, in order to specifically deregulate cellular pathways of their hosts. The impact of such PP2A targeting for biomedical search, and in further therapeutic developments against cancer, will also be discussed.
Protein phosphatase 2A (PP2A) is a large family of holoenzymes that comprises 1% of total cellular proteins and accounts for the majority of Ser/Thr phosphatase activity in eukaryotic cells. PP2A ...proteins are made of a core dimer, composed of a catalytic (C) subunit and a structural (A) subunit, in association with a third variable regulatory (B) subunit. Although initially considered as a constitutive housekeeping enzyme, PP2A is indeed highly regulated by post-translational modifications of its catalytic subunit or by the identity of a regulatory type B subunit, which determines substrate specificity, subcellular localization and enzymatic activity of a defined holoenzyme. During the two last decades, multiple studies of structural and functional regulation of PP2A holoenzymes by viral proteins led to the identification of critical pathways for both viral biology and tumorigenesis. To date a dozen of different viruses (ADN/ARN or retrovirus) have been identified that encode viral proteins associated to PP2A. In this review, we analyze a biological strategy, used by various viruses based on the targeting of PP2A enzymes by viral proteins, in order to specifically deregulate cellular pathways of their hosts. The impact of such PP2A targeting for biomedical search, and in further therapeutic developments against cancer, will also be discussed.
Les holoenzymes de la famille des protéine phosphatases 2A (PP2A) représentent 1 % des protéines de la cellule eucaryote et constituent la majorité de l’activité sérine/thréonine phosphatase de ces cellules. Ces holoenzymes contiennent un noyau dimérique appelé « core », formé d’une sous-unité catalytique (C) et d’une sous-unité structurale (A), auquel peut être associée une sous-unité régulatrice (B) variable. Initialement considérées comme des enzymes constitutivement actives, les PP2A peuvent être régulées par des modifications post-traductionnelles ou par l’induction des sous-unités régulatrices de type B qui en contrôlent l’activité. Lors des deux dernières décennies, des études basées sur l’interaction fonctionnelle de PP2A avec des protéines virales ont permis d’identifier des voies de signalisation critiques pour la biologie des virus et pour l’induction des processus tumoraux. À ce jour, on a déjà identifié une douzaine de virus différents (ADN/ARN et rétrovirus) codant pour des protéines virales associées à des PP2A. Nous analysons dans cette revue une stratégie basée sur l’interaction de protéines virales avec les protéines PP2A qui aboutit à une dérégulation spécifique de certaines voies de signalisation cellulaires. L’impact du ciblage viral des PP2A sur la recherche biomédicale et sur le développement de nouvelles approches thérapeutiques contre le cancer sera aussi discuté.
Protein phosphatase 2A (PP2A) is a large family of holoenzymes that comprises 1% of total cellular proteins and accounts for the majority of Ser/Thr phosphatase activity in eukaryotic cells. PP2A ...proteins are made of a core dimer, composed of a catalytic (C) subunit and a structural (A) subunit, in association with a third variable regulatory (B) subunit. Although initially considered as a constitutive housekeeping enzyme, PP2A is indeed highly regulated by post-translational modifications of its catalytic subunit or by the identity of a regulatory type B subunit, which determines substrate specificity, subcellular localization and enzymatic activity of a defined holoenzyme. During the two last decades, multiple studies of structural and functional regulation of PP2A holoenzymes by viral proteins led to the identification of critical pathways for both viral biology and tumorigenesis. To date a dozen of different viruses (ADN/ARN or retrovirus) have been identified that encode viral proteins associated to PP2A. In this review, we analyze a biological strategy, used by various viruses based on the targeting of PP2A enzymes by viral proteins, in order to specifically deregulate cellular pathways of their hosts. The impact of such PP2A targeting for biomedical search, and in further therapeutic developments against cancer, will also be discussed.
Les holoenzymes de la famille des protéine phosphatases 2A (PP2A) représentent 1 % des protéines de la cellule eucaryote et constituent la majorité de l’activité sérine/thréonine phosphatase de ces cellules. Ces holoenzymes contiennent un noyau dimérique appelé « core », formé d’une sous-unité catalytique (C) et d’une sous-unité structurale (A), auquel peut être associée une sous-unité régulatrice (B) variable. Initialement considérées comme des enzymes constitutivement actives, les PP2A peuvent être régulées par des modifications post-traductionnelles ou par l’induction des sous-unités régulatrices de type B qui en contrôlent l’activité. Lors des deux dernières décennies, des études basées sur l’interaction fonctionnelle de PP2A avec des protéines virales ont permis d’identifier des voies de signalisation critiques pour la biologie des virus et pour l’induction des processus tumoraux. À ce jour, on a déjà identifié une douzaine de virus différents (ADN/ARN et rétrovirus) codant pour des protéines virales associées à des PP2A. Nous analysons dans cette revue une stratégie basée sur l’interaction de protéines virales avec les protéines PP2A qui aboutit à une dérégulation spécifique de certaines voies de signalisation cellulaires. L’impact du ciblage viral des PP2A sur la recherche biomédicale et sur le développement de nouvelles approches thérapeutiques contre le cancer sera aussi discuté.
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