Biology subjects

Lafont, E.

Publications and source records attributed to Lafont, E..

3 recordsLinked to original sources

bioRxiv2026

Missense LMNA Variant Compromises Nuclear Integrity and Sarcomeric Remodeling in Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation, and pathogenic variants in LMNA are a well-established cause of inherited DCM. The LMNA gene encodes nuclear lamins A/C, which maintain nuclear integrity, regulate gene expression and mediate mechanotransduction. Here, we investigated the pathogenic consequences of the NM_170707.4(LMNA):c.274C>T NP_733821.1:p.(Leu92Phe) variant, previously associated with lipodystrophy features, using patient-derived induced pluripotent stem cells, differentiated into cardiomyocytes and show implication of LMNA in sarcomere remodeling and mitochondria efficiency. We generated iPSC lines from two DCM patients carrying LMNA p.Leu92Phe variant in heterozygous form and a healthy parental control. Cardiomyocytes differentiation efficiency was preserved, however, LMNAp.Leu92Phe iPSC-CMs exhibited laminopathies associated phenotypes, such as nuclear shape abnormalities and lamin A/C aggregation. Moreover, in vitro study revealed that LMNA p.Leu92Phe iPSC-CMs alter sarcomere reformation and decrease mitochondrial respiration after cardiomyocyte remodeling, which is associated with a worsening nuclear shape phenotype. Functional analyses highlight defects in calcium handling, thereby explaining arrhythmia and dilated cardiomyopathy features in patients. Our results show that the LMNA p.Leu92Phe variant compromises nuclear lamina integrity and disrupts functional cardiomyocyte properties, particularly during sarcomere remodeling, highlighting the long-term impact of this specific variant in LMNA-associated DCM.

genetics↗

bioRxiv2024

IRE1-dependent GOLIM4 expression controls protein secretion to modulate glioblastoma cell adhesion and migration

One of the main glioblastoma (GB) features is the diffuse migration of the tumor cells within the surrounding brain parenchyma, rendering almost impossible the complete tumor resection and irradiation, leading to inexorable lethal relapse of the disease. In the past years, we demonstrated that IRE1 (hereafter IRE1), one of the Endoplasmic Reticulum (ER) stress sensors, plays a key role in GB biology by impacting on immune infiltration, angiogenesis and tumor cell migration/invasion, all these features being linked to an alteration of protein secretion. In the present study, we investigated if and how IRE1 could regulate the functionality of the secretory machinery in GB cells and identified GOLIM4, a Golgi-associated molecule whose expression is regulated downstream of IRE1 through the transcription of XBP1s. Interestingly, GOLIM4 silencing led to decreased surface expression of multiple molecules including MHC class I molecules, growth factor receptors (PDGFRA and IL13RA2) and proteins involved in cell-cell adhesion (CD44, CD54, NCAM1), adhesion to matrix (ITGB1) or cell migration (CD90) without alteration of their encoding transcripts expression levels. Moreover, GOLIM4 silencing phenotypically affected GB cell-cell adhesion and cell migration in multiple models. Overall, we have described a novel IRE1/XBP1s/GOLIM4 operon that controls the secretion of specific proteins and impacts the tumor aggressiveness. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/619629v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@511636org.highwire.dtl.DTLVardef@18971f6org.highwire.dtl.DTLVardef@98ff81org.highwire.dtl.DTLVardef@ae7189_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

IRE1 RNase controls CD95-mediated cell death

Signalling by the Unfolded Protein Response (UPR) or by the Death Receptors (DR) represents cellular stress pathways frequently activated towards pro-tumoral outputs in cancer. Experimental evidence has highlighted functional links between the UPR and the DR TRAIL-R1/2. Herein, we demonstrate that the UPR sensor IRE1 controls the expression of CD95/Fas, another DR, and its cell death-inducing ability. Whereas CD95 is not a general determinant of ER stress-induced cell death, IRE1 RNase activity inhibition increased CD95 expression and exacerbated CD95L-induced cell death in glioblastoma (GB) and Triple-Negative Breast Cancer (TNBC) cell lines. In accordance, CD95 mRNA was identified as a target of Regulated IRE1-Dependent Decay of RNA (RIDD). Moreover, CD95 expression is elevated in TNBC and GB human tumours exhibiting low RIDD activity. Surprisingly, CD95 expression is also lower in XBP1s-low human tumour samples. We show that IRE1 RNase inhibition led to CD95 expression attenuation and reduced CD95-mediated hepatic toxicity in mice. In addition, overexpression of XBP1s increased CD95 expression and sensitized GB and TNBC cells to CD95L-induced cell death. Overall, these results demonstrate the tight IRE1-mediated control of CD95-dependent cell death signals in a dual manner through both RIDD and XBP1s, and they identify a novel, pharmacologically actionable link between IRE1 and CD95 signalling.

cell biology↗