Code for protein homeostasis imprinting across evolution

This folder contains all the code written to generate and analyse the data for both prokaryotes and eukaryotes:The code for the generation of prokaryotes data is included in the "prokaryotes" folder.The code for the generation of eukaryotes data is included in the "eukaryotes" folder.The code for the analysis is included in the "main_analysis" folder.The scripts core_classes.py, core_semantics.py, core_functions.py and heatmap.py are used in many subtasks, and they have been located in the main directory to be easily accessible.</p

draft

This folder contains all the code written to generate and analyse the data for both prokaryotes and eukaryotes:The code for the generation of prokaryotes data is included in the "prokaryotes" folder.The code for the generation of eukaryotes data is included in the "eukaryotes" folder.The code for the analysis is included in the "main_analysis" folder.The scripts core_classes.py, core_semantics.py, core_functions.py and heatmap.py are used in many subtasks, and they have been located in the main directory to be easily accessible.The data the are generated from all these scripts are included in the respective dataset folders in this collection.</p

Protein homeostasis imprinting across evolution

International audienceProtein homeostasis (a.k.a. proteostasis) is associated with the primary functions of life, and therefore with evolution. However, it is unclear how cellular proteostasis machines have evolved to adjust protein biogenesis needs to environmental constraints. Herein, we describe a novel computational approach, based on semantic network analysis, to evaluate proteostasis plasticity during evolution. We show that the molecular components of the proteostasis network (PN) are reliable metrics to deconvolute the life forms into Archaea, Bacteria and Eukarya and to assess the evolution rates among species. Semantic graphs were used as new criteria to evaluate PN complexity in 93 Eukarya, 250 Bacteria and 62 Archaea, thus representing a novel strategy for taxonomic classification, which provided information about species divergence. Kingdom-specific PN components were identified, suggesting that PN complexity may correlate with evolution. We found that the gains that occurred throughout PN evolution revealed a dichotomy within both the PN conserved modules and within kingdom-specific modules. Additionally, many of these components contribute to the evolutionary imprinting of other conserved mechanisms. Finally, the current study suggests a new way to exploit the genomic annotation of biomedical ontologies, deriving new knowledge from the semantic comparison of different biological systems

Non-apoptotic TRAIL function modulates NK cell activity during viral infection.

The role of death receptor signaling for pathogen control and infection-associated pathogenesis is multifaceted and controversial. Here, we show that during viral infection, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) modulates NK cell activity independently of its pro-apoptotic function. In mice infected with lymphocytic choriomeningitis virus (LCMV), Trail deficiency led to improved specific CD8+ T-cell responses, resulting in faster pathogen clearance and reduced liver pathology. Depletion experiments indicated that this effect was mediated by NK cells. Mechanistically, TRAIL expressed by immune cells positively and dose-dependently modulates IL-15 signaling-induced granzyme B production in NK cells, leading to enhanced NK cell-mediated T cell killing. TRAIL also regulates the signaling downstream of IL-15 receptor in human NK cells. In addition, TRAIL restricts NK1.1-triggered IFNγ production by NK cells. Our study reveals a hitherto unappreciated immunoregulatory role of TRAIL signaling on NK cells for the granzyme B-dependent elimination of antiviral T cells

A novel blood brain barrier-permeable IRE1 kinase inhibitor for adjuvant glioblastoma treatment in mice.

Inositol Requiring Enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease. It is a major mediator of the Unfolded Protein Response (UPR), which is activated upon endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues such as hypoxia or nutrient shortage and high metabolic/protein folding demand. To cope with those stresses, cancer cells can rely on IRE1 signaling as an adaptive mechanism. Herein, we report the discovery of novel IRE1 inhibitors identified through the structural exploration of the IRE1 kinase domain. We characterized the candidates in vitro and in cellular models and showed that all molecules inhibit IRE1 signaling and sensitize glioblastoma cells to the standard chemotherapeutic temozolomide (TMZ). We next selected a Blood-Brain Barrier (BBB) permeable inhibitor (Z4P) among these molecules and demonstrated its ability to inhibit Glioblastoma (GB) growth and to prevent relapse in vivo when administered together with TMZ. The hit compound disclosed in this study satisfies an unmet need for targeted, non-toxic IRE1 inhibitors and our results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB

A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment

Summary: Inositol-requiring enzyme 1 (IRE1) is a major mediator of the unfolded protein response (UPR), which is activated upon endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues, a stress overcome by relying on IRE1 signaling as an adaptive mechanism. Herein, we report the discovery of structurally new IRE1 inhibitors identified through the structural exploration of its kinase domain. Characterization in in vitro and in cellular models showed that they inhibit IRE1 signaling and sensitize glioblastoma (GB) cells to the standard chemotherapeutic, temozolomide (TMZ). Finally, we demonstrate that one of these inhibitors, Z4P, permeates the blood–brain barrier (BBB), inhibits GB growth, and prevents relapse in vivo when administered together with TMZ. The hit compound disclosed herein satisfies an unmet need for targeted, non-toxic IRE1 inhibitors and our results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB