Impact fonctionnel de mutations somatiques dans le gène ERN1 (IRE1ΑLPHA) dans les glioblastomes

In eukaryotic cells, alterations in the cellular microenvironment or mutations in the protein secretory pathway induce ER stress and activate an adaptive response termed UPR. The intracellular signals associated with UPR are transmitted from the ER lumen to the nucleus by three transmembrane proteins among which IRE1α also called ERN1. During ER stress, IRE1α oligomerizes, activating its kinase and endoribonuclease domains and a downstream complex intracellular signaling. Many studies linking the UPR to cancer point to IRE1α as a major player in tumorigenesis, particularly in the growth and vascularization of glioblastomas (GBM), although the precise mechanisms involved remain to be determined. Studies led in our laboratory have identified two targets of IRE1α endoribonuclease activity (RIDD): SPARC and PER1 as respective effectors of pro–angiogenic, pro-migratory and proproliferative effects of IRE1α in GBM. In addition, in recent years, IRE1α sequencing identified around fifty mutations, four of which have been identified in GBM biopsies. The expression of these four mutations, including A414T identified in the laboratory, in the U-87 MG cells, and implantation of these cells into mouse brain has highlighted the pro-tumoral role of the A414T mutation and the anti-tumor role of the P336L mutation. A414T oligomers stabilize IRE1α, over-activating downstream signaling pathways and leading to a faster growth and greater tumor vascularization. Thus, our work confirms that IRE1α is a central regulator of GBM development and may be a prognostic marker and therapeutic target in GBM.Dans les cellules eucaryotes, des altérations du microenvironnement cellulaire ou desmutations des protéines de la voie de sécrétion induisent un stress du RE et activent uneréponse adaptative nommée UPR. Les signaux intracellulaires associés à l’UPR sont transmisde la lumière du RE vers le noyau par trois protéines transmembranaires dont IRE1α aussiappelée ERN1. Lors d'un stress du RE, IRE1α s'oligomérise, activant ses domaines kinase etendoribonucléase desquelles découle une signalisation intracellulaire complexe. Denombreuses études reliant l'UPR au cancer désignent IRE1α comme un acteur majeur de latumorigenèse, en particulier dans la croissance et la vascularisation des glioblastomes (GBM),bien que les mécanismes précis mis en jeu restent à déterminer. Des études menées dans notrelaboratoire ont identifié deux cibles de l'activité endoribonucléase d'IRE1α (RIDD) : SPARCet PER1, comme effecteurs respectifs des effets pro-migratoire, pro-angiogénique et proprolifératifd'IRE1α dans les GBM. De plus, ces dernières années, le séquençage d'IRE1α apermis d'identifier environ cinquante mutations, dont quatre non silencieuses ont étéidentifiées dans des biopsies de GBM. L'expression de ces quatre mutations, dont A414Tidentifiée dans le laboratoire, dans les cellules U-87 MG, et l'implantation de ces cellules dansle cerveau de souris a permis de mettre en évidence le rôle pro tumoral de la mutation A414Tet le rôle anti-tumoral de la mutation P336L. A414T stabilise les oligomères d'IRE1α, suractivantles voies de signalisation en aval et conduisant à une croissance plus rapide et unevascularisation plus importante des tumeurs. Ainsi, nos travaux confirment qu'IRE1α est unrégulateur central du développement des GBM et pourrait constituer un marqueur pronostic etune cible thérapeutique des GBM

Impact of functional somatic mutations in the gene ERN1 (IRE1ALPHA) in glioblastomas

Dans les cellules eucaryotes, des altérations du microenvironnement cellulaire ou desmutations des protéines de la voie de sécrétion induisent un stress du RE et activent uneréponse adaptative nommée UPR. Les signaux intracellulaires associés à l’UPR sont transmisde la lumière du RE vers le noyau par trois protéines transmembranaires dont IRE1α aussiappelée ERN1. Lors d'un stress du RE, IRE1α s'oligomérise, activant ses domaines kinase etendoribonucléase desquelles découle une signalisation intracellulaire complexe. Denombreuses études reliant l'UPR au cancer désignent IRE1α comme un acteur majeur de latumorigenèse, en particulier dans la croissance et la vascularisation des glioblastomes (GBM),bien que les mécanismes précis mis en jeu restent à déterminer. Des études menées dans notrelaboratoire ont identifié deux cibles de l'activité endoribonucléase d'IRE1α (RIDD) : SPARCet PER1, comme effecteurs respectifs des effets pro-migratoire, pro-angiogénique et proprolifératifd'IRE1α dans les GBM. De plus, ces dernières années, le séquençage d'IRE1α apermis d'identifier environ cinquante mutations, dont quatre non silencieuses ont étéidentifiées dans des biopsies de GBM. L'expression de ces quatre mutations, dont A414Tidentifiée dans le laboratoire, dans les cellules U-87 MG, et l'implantation de ces cellules dansle cerveau de souris a permis de mettre en évidence le rôle pro tumoral de la mutation A414Tet le rôle anti-tumoral de la mutation P336L. A414T stabilise les oligomères d'IRE1α, suractivantles voies de signalisation en aval et conduisant à une croissance plus rapide et unevascularisation plus importante des tumeurs. Ainsi, nos travaux confirment qu'IRE1α est unrégulateur central du développement des GBM et pourrait constituer un marqueur pronostic etune cible thérapeutique des GBM.In eukaryotic cells, alterations in the cellular microenvironment or mutations in the protein secretory pathway induce ER stress and activate an adaptive response termed UPR. The intracellular signals associated with UPR are transmitted from the ER lumen to the nucleus by three transmembrane proteins among which IRE1α also called ERN1. During ER stress, IRE1α oligomerizes, activating its kinase and endoribonuclease domains and a downstream complex intracellular signaling. Many studies linking the UPR to cancer point to IRE1α as a major player in tumorigenesis, particularly in the growth and vascularization of glioblastomas (GBM), although the precise mechanisms involved remain to be determined. Studies led in our laboratory have identified two targets of IRE1α endoribonuclease activity (RIDD): SPARC and PER1 as respective effectors of pro–angiogenic, pro-migratory and proproliferative effects of IRE1α in GBM. In addition, in recent years, IRE1α sequencing identified around fifty mutations, four of which have been identified in GBM biopsies. The expression of these four mutations, including A414T identified in the laboratory, in the U-87 MG cells, and implantation of these cells into mouse brain has highlighted the pro-tumoral role of the A414T mutation and the anti-tumor role of the P336L mutation. A414T oligomers stabilize IRE1α, over-activating downstream signaling pathways and leading to a faster growth and greater tumor vascularization. Thus, our work confirms that IRE1α is a central regulator of GBM development and may be a prognostic marker and therapeutic target in GBM

Dual IRE1 RNase functions dictate glioblastoma development

Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1 alpha (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1-dependent decay (RIDD) of RNA. Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1-dependent gene expression signatures that were confronted to human GBM transcriptomes. This approach allowed us to demonstrate the antagonistic roles of XBP1 mRNA splicing and RIDD on tumor outcomes, mainly through selective remodeling of the tumor stroma. This study provides the first demonstration of a dual role of IRE1 downstream signaling in cancer and opens a new therapeutic window to abrogate tumor progression.Institut National du Cancer (INCa PLBIO: 2017-148 PLBIO: 2015-111 INCA_ 7981 La Ligue Contre le Cancer (Comite des Landes, LARGE project) PHC Maimonide EU H MSCA ITN-675448 RISE-734749 Region Bretagne "AAP CRITT sante" French government Fondation pour la Recherche Medicale Fondation de France Region Bretagn

Control of the Unfolded Protein Response in Health and Disease

International audienceThe unfolded protein response (UPR) is an integrated, adaptive biochemical process that is inextricably linked with cell homeostasis and paramount to maintenance of normal physiological function. Prolonged accumulation of improperly folded proteins in the endoplasmic reticulum (ER) leads to stress. This is the driving stimulus behind the UPR. As such, prolonged ER stress can push the UPR past beneficial functions such as reduced protein production and increased folding and clearance to apoptotic signaling. The UPR is thus contributory to the commencement, maintenance, and exacerbation of a multitude of disease states, making it an attractive global target to tackle conditions sorely in need of novel therapeutic intervention. The accumulation of information of screening tools, readily available therapies, and potential pathways to drug development is the cornerstone of informed clinical research and clinical trial design. Here, we review the UPR's involvement in health and disease and, beyond providing an in-depth description of the molecules found to target the three UPR arms, we compile all the tools available to screen for and develop novel therapeutic agents that modulate the UPR with the scope of future disease intervention

Endoplasmic reticulum homeostasis-From molecules to organisms: Report on the 14th International Calreticulin Workshop, Saint Malo, France

International audienceThe Calreticulin Workshop, initiated in 1994 by Marek Michalak in Banff (Alberta, Canada), was first organized to be an informal scientific meeting attended by researchers working on diverse biological questions related to functions associated with the endoplasmic reticulum (ER)-resident lectin-like chaperone and applied to a wide range of biological systems and models. Since then, this workshop has broadened the range of topics to cover all ER-related functions, has become international and has been held in Canada, Chile, Denmark, Italy, Switzerland, UK, USA, Greece and this year in France. Each conference, which is organized every other year (pending world-wide pandemic), generally attracts between 50 and 100 participants, including both early career researchers and international scientific leaders to favour discussions and exchanges. Over the years, the International Calreticulin Workshop has become an important gathering of the calreticulin and ER communities as a whole. The 14th International Calreticulin Workshop occurred from May 9-12 in St-Malo, Brittany, France, and has been highlighted by its rich scientific content and open-minded discussions held in a benevolent atmosphere. The 15th International Calreticulin Workshop will be organized in 2025 in Brussels, Belgium