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1.
Commun Biol ; 5(1): 456, 2022 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-35550602

RESUMO

Mechanosignaling, initiated by extracellular forces and propagated through the intracellular cytoskeletal network, triggers signaling cascades employed in processes as embryogenesis, tissue maintenance and disease development. While signal transduction by transcription factors occurs downstream of cellular mechanosensing, little is known about the cell intrinsic mechanisms that can regulate mechanosignaling. Here we show that transcription factor PREP1 (PKNOX1) regulates the stiffness of the nucleus, the expression of LINC complex proteins and mechanotransduction of YAP-TAZ. PREP1 depletion upsets the nuclear membrane protein stoichiometry and renders nuclei soft. Intriguingly, these cells display fortified actomyosin network with bigger focal adhesion complexes resulting in greater traction forces at the substratum. Despite the high traction, YAP-TAZ translocation is impaired indicating disrupted mechanotransduction. Our data demonstrate mechanosignaling upstream of YAP-TAZ and suggest the existence of a transcriptional mechanism actively regulating nuclear membrane homeostasis and signal transduction through the active engagement/disengagement of the cell from the extracellular matrix.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Fatores de Transcrição , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Mecanotransdução Celular/fisiologia , Membrana Nuclear/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteínas de Sinalização YAP
2.
Nat Commun ; 11(1): 2122, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358486

RESUMO

Cell polarity refers to the intrinsic asymmetry of cells, including the orientation of the cytoskeleton. It affects cell shape and structure as well as the distribution of proteins and organelles. In migratory cells, front-rear polarity is essential and dictates movement direction. While the link between the cytoskeleton and nucleus is well-studied, we aim to investigate if front-rear polarity can be transmitted to the nucleus. We show that the knock-down of emerin, an integral protein of the nuclear envelope, abolishes preferential localization of several nuclear proteins. We propose that the frontally biased localization of the endoplasmic reticulum, through which emerin reaches the nuclear envelope, is sufficient to generate its observed bias. In primary emerin-deficient myoblasts, its expression partially rescues the polarity of the nucleus. Our results demonstrate that front-rear cell polarity is transmitted to the nucleus and that emerin is an important determinant of nuclear polarity.


Assuntos
Núcleo Celular/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Nucleares/metabolismo , Western Blotting , Linhagem Celular , Núcleo Celular/ultraestrutura , Imunofluorescência , Humanos , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Mioblastos/metabolismo , Mioblastos/ultraestrutura , Membrana Nuclear/metabolismo , Membrana Nuclear/ultraestrutura , Interferência de RNA
3.
Int J Infect Dis ; 71: 53-55, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29653201

RESUMO

OBJECTIVES: The serological detection of IgM antibodies is the most widely used test to diagnose scrub typhus infection. However, the kinetics of IgM and IgG antibodies post-infection remain elusive, which could contribute to false positivity. The objective of this study was to document the nature of the evolution of these antibody titres after infection. METHODS: Adult patients previously confirmed to have scrub typhus by IgM ELISA, positive PCR, or both, were included in this cross-sectional study. The levels of IgM and IgG antibodies in serum samples were tested using an ELISA and the distribution curve was plotted. RESULTS: Two hundred and three patients were included in this study. Post-infection serum sampling was done between 1 month and 46 months after documented infection. IgM levels declined gradually but remained elevated above the diagnostic cut-off for up to 12 months post-infection. However, IgG levels continued to rise reaching a peak at 10 months, followed by a gradual decline over several months. In the majority of cases, the IgG levels remained above the cut-off threshold for more than 36 months. CONCLUSIONS: Clinicians need to be cautious in using a single serum sample for the detection of IgM to diagnose scrub typhus, as it remains elevated for up to 12 months after the infection, whereas the serum IgG level could be used as an indicator of past infection.


Assuntos
Anticorpos Antibacterianos/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Tifo por Ácaros/diagnóstico , Adulto , Estudos Transversais , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Tifo por Ácaros/imunologia
4.
Sci Rep ; 8(1): 3198, 2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29453404

RESUMO

The synthesis of middle-to-late-replicating DNA can be affected independently of the rest of the genome by down-regulating the tumor suppressor PREP1 (PKNOX1). Indeed, DNA combing shows that PREP1 down-regulation affects DNA replication rate, increases the number of simultaneously firing origins and the asymmetry of DNA replication, leading to DNA damage. Genome-wide analysis of replication timing by Repli-seq shows that, upon PREP1 down-regulation, 25% of the genome is replicated earlier in the S-phase. The targeted DNA sequences correspond to Lamin-Associated Domains (LADs), and include late-replicating (LRRs) and temporal transition regions (TTRs). Notably, the distribution of PREP1 DNA binding sites and of its target genes indicates that DNA replication defects are independent of the overall PREP1 transcriptional activity. Finally, PREP1 down-regulation causes a substantial decrease in Lamin B1 levels. This suggests that DNA is released from the nuclear lamina earlier than in the control cells and is available for replication, thus explaining timing defects and DNA damage.This is the first evidence that the replication timing of a specific fraction of the human genome is affected by PREP1 tumor suppressor. This previously unknown function might significantly contribute to the genomic instability observed in human tumors.


Assuntos
Período de Replicação do DNA/fisiologia , Genes Supressores de Tumor/fisiologia , Instabilidade Genômica , Proteínas de Homeodomínio/fisiologia , Sítios de Ligação , Dano ao DNA , Período de Replicação do DNA/genética , Regulação da Expressão Gênica , Genoma Humano , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Lamina Tipo B/metabolismo
5.
Int J Dev Biol ; 62(11-12): 819-825, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30604851

RESUMO

Prep1 (pKnox1) is a homeodomain transcription factor of the TALE superclass whose members can act as co-factors of Hox. Prep1 is essential for embryogenesis, but in the adult it also acts as a tumor suppressor. We describe and analyze here the available mutant mice, their phenotypes and a few discordant cases. Moreover we specify the basic rules underlying the binding of Prep1 and its TALE partners to DNA, and their plasticity during embryonic development. We finally review recent data on Prep1 which indicate a very basic cellular function at the level of DNA replication and DNA damage.


Assuntos
Dano ao DNA , Proteínas de Homeodomínio/genética , Animais , Desenvolvimento Embrionário/genética , Feminino , Proteínas de Homeodomínio/metabolismo , Camundongos , Camundongos Transgênicos , Gravidez
6.
J Immunol ; 190(1): 97-105, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23225886

RESUMO

Lineage-committed T effectors generated in response to Ag during the inflammatory phase are destined to die during termination of the immune response. We present evidence to suggest that molecular signatures of lineage commitment are reflected in apoptotic cascades activated in CD4(+) T effectors. Exemplifying this, ablation of inducible NO synthase (iNOS) protected effector-memory T (TEM) cells, but not T(Naive) or central-memory T cells, activated in vitro, from apoptosis triggered by cytokine deprivation. Furthermore, attrition of T effectors generated in the secondary, but not the primary, response to Ag was substantially reduced in mice, which received iNOS inhibitors. Distinct patterns of iNOS expression were revealed in wild-type TEM effectors undergoing apoptosis, and ablation of iNOS protein in primary and TEM wild-type effectors confirmed observations made in iNOS(-/-) cells. Describing molecular correlates of this dependence, mitochondrial damage, activation of the protein Bax, and release from mitochondria of the apoptosis-inducing factor were selectively abrogated in iNOS(-/-) TEM effectors. Suggesting that iNOS dependence was linked to the functional identity of T cell subsets, both iNOS induction and apoptosis were compromised in IFN-γ(-/-) TEM effectors, which mirrored the response patterns of iNOS(-)(/)(-) TEM. Collectively, these observations suggest that programs regulating deletion and differentiation are closely integrated and likely encoded during lineage commitment of T effectors.


Assuntos
Apoptose/imunologia , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Linhagem da Célula/imunologia , Memória Imunológica , Óxido Nítrico Sintase Tipo II/fisiologia , Subpopulações de Linfócitos T/enzimologia , Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular/imunologia , Células Cultivadas , Feminino , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Óxido Nítrico Sintase Tipo II/deficiência , Óxido Nítrico Sintase Tipo II/genética , Subpopulações de Linfócitos T/citologia
7.
J Exp Med ; 206(7): 1515-23, 2009 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-19546249

RESUMO

Cellular dependence on growth factors for survival is developmentally programmed and continues in adult metazoans. Antigen-activated T cell apoptosis in the waning phase of the immune response is thought to be triggered by depletion of cytokines from the microenvironment. T cell apoptosis resulting from cytokine deprivation is mediated by reactive oxygen species (ROS), but their source and position in the apoptotic cascade is poorly understood. RNA interference approaches implicated the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in neglect-induced apoptosis in T cells. Using mice deficient for the catalytic subunit gp91(phox) to characterize the molecular link to activated T cell apoptosis, we show that gp91(phox)-deficient T (T(-/-)) cells generated mitochondrial superoxide but had diminished hydrogen peroxide production in response to neglect, which, in turn, regulated Jun N-terminal kinase-dependent Bax activation and apoptosis. Activated T(-/-) cells were distinguished by improved survival after activation by superantigens in vivo, adoptive transfers into congenic hosts, and higher recall responses after immunization. Thus, the NADPH oxidase may regulate adaptive immunity in addition to its previously well-characterized role in the innate response.


Assuntos
Citocinas/imunologia , Homeostase , Ativação Linfocitária , NADPH Oxidases/metabolismo , Linfócitos T/enzimologia , Linfócitos T/imunologia , Animais , Apoptose/imunologia , Células Cultivadas , Ativação Enzimática , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , NADPH Oxidase 2 , NADPH Oxidases/genética , NADPH Oxidases/imunologia , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Receptores CCR7/genética , Receptores CCR7/imunologia , Linfócitos T/citologia , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/imunologia
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