Phosphorylation Codes in IRS-1 and IRS-2 Are Associated with the Activation/Inhibition of Insulin Canonical Signaling Pathways.

Insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) are signaling adaptor proteins that participate in canonical pathways, where insulin cascade activation occurs, as well as in non-canonical pathways, in which phosphorylation of substrates is carried out by a diverse array of receptors including integrins, cytokines, steroid hormones, and others. IRS proteins are subject to a spectrum of post-translational modifications essential for their activation, encompassing phosphorylation events in distinct tyrosine, serine, and threonine residues. Tyrosine residue phosphorylation is intricately linked to the activation of the insulin receptor cascade and its interaction with SH2 domains within a spectrum of proteins, including PI3K. Conversely, serine residue phosphorylation assumes a different function, serving to attenuate the effects of insulin. In this review, we have identified over 50 serine residues within IRS-1 that have been reported to undergo phosphorylation orchestrated by a spectrum of kinases, thereby engendering the activation or inhibition of different signaling pathways. Furthermore, we delineate the phosphorylation of over 10 distinct tyrosine residues at IRS-1 or IRS-2 in response to insulin, a process essential for signal transduction and the subsequent activation of PI3K.

IL-34-Dependent Intrarenal and Systemic Mechanisms Promote Lupus Nephritis in MRL-Faslpr Mice.

BACKGROUND: In people with SLE and in the MRL-Faslpr lupus mouse model, macrophages and autoantibodies are central to lupus nephritis. IL-34 mediates macrophage survival and proliferation, is expressed by tubular epithelial cells (TECs), and binds to the cFMS receptor on macrophages and to a newly identified second receptor, PTPRZ. METHODS: To investigate whether IL-34-dependent intrarenal and systemic mechanisms promote lupus nephritis, we compared lupus nephritis and systemic illness in MRL-Faslpr mice expressing IL-34 and IL-34 knockout (KO) MRL-Faslpr mice. We also assessed expression of IL-34 and the cFMS and PTPRZ receptors in patients with lupus nephritis. RESULTS: Intrarenal IL-34 and its two receptors increase during lupus nephritis in MRL-Faslpr mice. In knockout mice lacking IL-34, nephritis and systemic illness are suppressed. IL-34 fosters intrarenal macrophage accumulation via monocyte proliferation in bone marrow (which increases circulating monocytes that are recruited by chemokines into the kidney) and via intrarenal macrophage proliferation. This accumulation leads to macrophage-mediated TEC apoptosis. We also found suppression of circulating autoantibodies and glomerular antibody deposits in the knockout mice. This is consistent with fewer activated and proliferating intrarenal and splenic B cells in mice lacking IL-34, and with our novel discovery that PTPRZ is expressed by macrophages, B and T cells. These findings appear translatable to human patients with lupus nephritis, whose expression of IL-34, cFMS, and PTPRZ is similar to that seen in the MRL-Faslpr lupus mouse model. Moreover, expression of IL-34 in TECs correlates with disease activity. CONCLUSIONS: IL-34 is a promising novel therapeutic target for patients with lupus nephritis.

Cytomegalovirus glycoprotein B genotypes in Mexican children and women.

OBJECTIVE: Cytomegalovirus (CMV) is widely distributed and constitutes the main cause of congenital infections worldwide. CMV transmission during pregnancy represents one of the major impacts of this virus on public health. This study aimed at assessing glycoprotein B (gB) CMV genotypes in Mexican children and pregnant women, since there is limited information regarding CMV genomic diversity in Mexico. METHODS: We analyzed CMV strains detected in Mexican children (n = 38) and women (n = 38) between 2001 and 2012. A fragment of the gB gene was amplified and sequenced, and genotypes were defined based on prototype sequences. RESULTS: The gB1 genotype was detected more frequently in children (68.4%) compared to women (31.6%; p = 0.0028), while genotype 2 was more common in women (65.8%) compared to children (26.3%, p = 0.0012). Genotype 3 was uncommon in both groups (5.3 and 2.6%). Nucleotide sequences exhibited a high degree of similarity to prototype strains. However, we identified 17 distinct sequences that resulted in changes in the encoded amino acid sequence in four strains. CONCLUSIONS: gB1 and gB2 are the most common strains associated with CMV infection in Mexican children and women. In addition, we found that the frequency for each genotype differed amongst them, possibly due to variability in transmission or reactivation dynamics.

[Modulation of apoptosis by cytomegalovirus, from the perspective of the central nervous system]. / Modulación de la apoptosis por cytomegalovirus en la perspectiva del sistema nervioso central.

Apoptosis is one of the most effective mechanisms against the spread of pathogens such as viruses. However, viruses have developed measures to counter the protective role of apoptosis in infected cells. Cytomegalovirus (CMV) represents the major cause of congenital infection worldwide triggering important damage in the developing central nervous system (CNS). Several mechanisms of apoptosis prevention during CMV infection have been described, among them, viral proteins and RNAs are capable of prevent apoptosis by the intrinsic and extrinsic pathways as well as the one mediated by stress in the endoplasmic reticulum. Nevertheless, the CMV pro-apoptotic effect remains enigmatic and it has been suggested as a bystander effect in non-infected cells. This review summarizes the mechanisms by which CMV modulates the signaling pathways involved in apoptosis. It also includes a brief description of the permissiveness of the CNS to CMV infection and the generated cell death after infection, which may relate to the observed damage during a congenital infection.

Modulación de la apoptosis por cytomegalovirus en la perspectiva del sistema nervioso central / Modulation of apoptosis by cytomegalovirus, from the perspective of the central nervous system

Apoptosis is one of the most effective mechanisms against the spread of pathogens such as viruses. However, viruses have developed measures to counter the protective role of apoptosis in infected cells. Cytomegalovirus (CMV) represents the major cause of congenital infection worldwide triggering important damage in the developing central nervous system (CNS). Several mechanisms of apoptosis prevention during CMV infection have been described, among them, viral proteins and RNAs are capable of prevent apoptosis by the intrinsic and extrinsic pathways as well as the one mediated by stress in the endoplasmic reticulum. Nevertheless, the CMV pro-apoptotic effect remains enigmatic and it has been suggested as a bystander effect in non-infected cells. This review summarizes the mechanisms by which CMV modulates the signaling pathways involved in apoptosis. It also includes a brief description of the permissiveness of the CNS to CMV infection and the generated cell death after infection, which may relate to the observed damage during a congenital infection.

La apoptosis representa uno de los mecanismos de defensa más eficaces frente a la propagación de patógenos como lo son los virus. No obstante, éstos han desarrollado medidas para contrarrestar el papel protector de la apoptosis en las células infectadas. Citomegalovirus (CMV) es considerado la principal causa de infecciones congénitas a nivel mundial, afectando de forma importante el sistema nervioso central (SNC) en desarrollo. Diversos mecanismos de prevención de apoptosis durante la infección por CMV han sido descritos, entre los cuales, se encuentran proteínas y ARNs virales capaces de evitar la apoptosis por las vías intrínseca, extrínseca y la mediada por estrés del retículo endoplásmico. Sin embargo, aún representa un enigma el efecto pro-apoptótico de CMV que se sugiere actúe como un efecto espectador sobre las células no infectadas. En el presente trabajo se ofrece una revisión de los mecanismos mediante los cuales CMV modula las vías de señalización involucradas en la apoptosis. Asimismo se incluye una breve descripción de la permisividad del SNC a la infección por CMV y sobre la muerte celular generada tras la infección, que pueden relacionarse con el daño observado durante una infección congénita.