Biology subjects

Lalou, A.

Publications and source records attributed to Lalou, A..

6 recordsLinked to original sources

bioRxiv2024

Uncoupling the functional roles of Coronavirus Nsp1

When host cells are infected with coronaviruses, the first viral protein produced is Nsp1. This protein inhibits host protein synthesis and induces host mRNA degradation to enhance viral proliferation. Despite its critical role, the mechanism by which Nsp1 mediates cellular mRNA degradation remains unclear. In this study, we use cell-free translation to address how the host mRNA stability is regulated by Nsp1. We reveal that SARS-CoV-2 Nsp1 binding to the ribosome is enough to trigger mRNA degradation independently of ribosome collisions or active translation. MERS-CoV Nsp1 inhibits translation without triggering degradation, highlighting mechanistic differences between the two Nsp1 counterparts. Nsp1 and viral mRNAs appear to co-evolve, rendering viral mRNAs immune to Nsp1-mediated degradation in SARS-CoV-2, MERS-CoV and Bat-Hp viruses. By providing new insights into the mode of action of Nsp1, our study helps to understand the biology of Nsp1 better and find new strategies for therapeutic targeting against coronaviral infections. SignificanceO_LICell-free assays allow the decoupling of Nsp1-mediated translation inhibition from RNA degradation. C_LIO_LINsp1 interaction with the ribosome is crucial for mRNA degradation, but active translation is not required. C_LIO_LISARS-CoV-2 Nsp1 induces mRNA degradation, while MERS-CoV Nsp1 inhibits translation without triggering degradation. C_LIO_LI5UTR-specific protection of viral mRNAs from Nsp1 indicates a co-evolutionary adaptation between the two features C_LI

molecular biology↗

bioRxiv2024

High-content phenotypic analysis of a C. elegans recombinant inbred population identifies genetic and molecular regulators of lifespan

Lifespan is influenced by complex interactions between genetic and environmental factors. Studying those factors in model organisms of a single genetic background limits their translational value for humans. Here, we mapped lifespan determinants in 85 genetically diverse C. elegans recombinant intercross advanced inbred lines (RIAILs). We assessed molecular profiles - transcriptome, proteome, and lipidome - and life-history traits, including lifespan, development, growth dynamics, and reproduction. RIAILs exhibited large variations in lifespan, which positively correlated with developmental time. Among the top candidates obtained from multi-omics data integration and QTL mapping, we validated known and novel longevity modulators, including rict-1, gfm-1 and mltn-1. We translated their relevance to humans using UK Biobank data and showed that variants in RICTOR and GFM1 are associated with an elevated risk of age-related heart disease, dementia, diabetes, kidney, and liver diseases. We organized our dataset as a resource (https://lisp-lms.shinyapps.io/RIAILs/) that allows interactive explorations for new longevity targets.

systems biology↗

bioRxiv2023

Inhibition of CERS1 in skeletal muscle exacerbates age-related muscle dysfunction

Age-related muscle wasting and dysfunction render the elderly population vulnerable and incapacitated, while underlying mechanisms are poorly understood. Here, we implicate the CERS1 enzyme of the de novo sphingolipid synthesis pathway in the pathogenesis of age-related skeletal muscle impairment. In humans, CERS1 abundance declines with aging in skeletal muscle cells and, correlates with biological pathways involved in muscle function and myogenesis. Furthermore, CERS1 is upregulated during myogenic differentiation. Pharmacological or genetic inhibition of CERS1 in aged mice blunts myogenesis and deteriorates aged skeletal muscle mass and function, which is associated with the occurrence of morphological features typical of inflammation and fibrosis. Ablation of the CERS1 orthologue lagr-1 in C. elegans similarly exacerbates the age-associated decline in muscle function and integrity. We discover genetic variants reducing CERS1 expression in human skeletal muscle and Mendelian randomization analysis in the UK biobank cohort shows that these variants reduce muscle grip strength and overall health. In summary, our findings link age-related impairments in muscle function to a reduction in CERS1, thereby underlining the importance of the sphingolipid biosynthesis pathway in age-related muscle homeostasis.

physiology↗

bioRxiv2022

A lysosomal surveillance response (LySR) that reduces proteotoxicity and extends healthspan

Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homeostasis and health. Here, we discovered an adaptive lysosomal transcriptional response that we termed the Lysosomal Surveillance Response (LySR). Typified by the induction of a large group of transcripts involved in lysosomal function and proteolysis, the LySR can be triggered by silencing of specific vacuolar H+-ATPase subunits in Caenorhabditis elegans. Notably, LySR activation enhances the clearance of protein aggregates in worm models of Alzheimers and Huntingtons disease and amyotrophic lateral sclerosis, thereby boosting fitness and extending lifespan. The GATA transcription factor, ELT-2, regulates the LySR program as well as its associated beneficial effects. In mammalian cells, overexpression of GATA4/GATA6, the mammalian orthologs of ELT-2, is sufficient to induce the expression of multiple lysosome-specific proteases and alleviate proteotoxicity. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan. HighlightsO_LIRNAi of specific v-ATPase subunits extends C. elegans lifespan and activates LySR C_LIO_LIGATA transcription factor ELT-2 regulates LySR and LySR-associated lifespan extension C_LIO_LILySR activation reduces protein aggregates and extends worm healthspan C_LIO_LIOverexpression of GATA4/GATA6 alleviates amyloid-{beta} proteotoxicity in mammalian cells C_LI

cell biology↗

bioRxiv2021

Multi-omics analysis identifies essential regulators of mitochondrial stress response in two wild-type C. elegans strains

The mitochondrial unfolded protein response (UPRmt) is a promising pharmacological target for aging and age-related diseases. However, the integrative analysis of the impact of UPRmt activation on different layers of signaling in animals with a different genetic background is lacking. In this study, we applied systems approaches to investigate the effect of UPRmt induced by administering doxycycline (Dox) on transcriptome, proteome, lipidome, and metabolome in two genetically divergent C. elegans strains. We found that Dox prolongs lifespan of both worm strains through pathways in both shared and strain-specific manners. From the integrated omics datasets, we observed a strong impact of Dox on mitochondrial functions, detected upregulated defense response and lipid metabolism, identified decreased triglycerides and lowered metabolome profiles in both strains. This conserved phenomic footprint has great translational value as it indicates that the beneficial effects of Dox-induced UPRmt on health and lifespan are consistent across different genetic backgrounds.

systems biology↗

bioRxiv2021

An improved ChEC-seq method accurately maps the genome-wide binding of transcription coactivators and sequence-specific transcription factors

Mittal and colleagues have raised questions about mapping transcription factor locations on DNA using the MNase-based ChEC-seq method (Mittal et al., 2021). Partly due to this concern, we modified the experimental conditions of the MNase cleavage step and subsequent computational analyses, resulting in more stringent conditions for mapping protein-DNA interactions (Donczew et al., 2020). The revised method (dx.doi.org/10.17504/protocols.io.bizgkf3w) answers questions raised by Mittal et al. and, without changing earlier conclusions, identified widespread promoter binding of the transcription coactivators TFIID and SAGA at active genes. The revised method is also suitable for accurately mapping the genome-wide locations of DNA sequence-specific transcription factors.

genomics↗