RESUMEN
Chronic inflammatory processes in the intestine result in serious conditions such as inflammatory bowel disease (IBD) and cancer. An increased detection of cytoplasmic DNA sensors has been reported in the IBD colon mucosa, suggesting their contribution in mucosal inflammation. Yet, the mechanisms altering DNA homeostasis and triggering the activation of DNA sensors remain poorly understood. In this study, we show that the epigenetic regulator HP1γ plays a role in preserving nuclear envelope and genomic integrity in enterocytic cells, thereby protecting against the presence of cytoplasmic DNA. Accordingly, HP1 loss of function led to the increased detection of cGAS/STING, a cytoplasmic DNA sensor that triggers inflammation. Thus, in addition to its role as a transcriptional silencer, HP1γ may also exert anti-inflammatory properties by preventing the activation of the endogenous cytoplasmic DNA response in the gut epithelium.
Asunto(s)
Adenocarcinoma , Neoplasias del Colon , Enfermedades Inflamatorias del Intestino , Humanos , Membrana Nuclear/metabolismo , Transducción de Señal , Adenocarcinoma/genética , Neoplasias del Colon/genética , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Inflamación/patología , ADN , GenómicaRESUMEN
Defects in RNA splicing have been linked to human disorders, but remain poorly explored in inflammatory bowel disease (IBD). Here, we report that expression of the chromatin and alternative splicing regulator HP1γ is reduced in ulcerative colitis (UC). Accordingly, HP1γ gene inactivation in the mouse gut epithelium triggers IBD-like traits, including inflammation and dysbiosis. In parallel, we find that its loss of function broadly increases splicing noise, favoring the usage of cryptic splice sites at numerous genes with functions in gut biology. This results in the production of progerin, a toxic splice variant of prelamin A mRNA, responsible for the Hutchinson-Gilford Progeria Syndrome of premature aging. Splicing noise is also extensively detected in UC patients in association with inflammation, with progerin transcripts accumulating in the colon mucosa. We propose that monitoring HP1γ activity and RNA splicing precision can help in the management of IBD and, more generally, of accelerated aging.
Asunto(s)
Colitis Ulcerosa , Progeria , Humanos , Ratones , Animales , Homólogo de la Proteína Chromobox 5 , Colitis Ulcerosa/genética , Empalme del ARN/genética , Progeria/genética , Progeria/metabolismo , InflamaciónRESUMEN
Long non-coding RNAs (lncRNAs) play a central role in the regulation of gene expression. Although they were initially described as mRNA-like transcripts not encoding proteins, global approaches such as ribosome profiling have shown that they frequently associate with ribosomes, opening the possibility that lncRNAs are a source of cryptic translation events with functional roles. Recent studies have shed more light on small ORFs borne by lncRNAs and encoding short peptides potentially involved in infectious immunity. This review outlines the main strategies used to determine the coding potential of lncRNAs and discusses our emerging understanding of the implication of the encoded peptides in infectious diseases.
Asunto(s)
Enfermedades Transmisibles/genética , Enfermedades Transmisibles/inmunología , Péptidos/inmunología , ARN Largo no Codificante/inmunología , ARN Largo no Codificante/metabolismo , Ribosomas/metabolismo , Animales , Enfermedades Transmisibles/metabolismo , Perfilación de la Expresión Génica , Humanos , Sistemas de Lectura Abierta/genética , Péptidos/metabolismo , Biosíntesis de Proteínas/genética , Biosíntesis de Proteínas/inmunología , Proteómica , ARN Largo no Codificante/química , ARN Largo no Codificante/genéticaRESUMEN
Old long-lived proteins contain dehydroalanine (Dha) and dehydrobutyrine (Dhb), two amino acids engendered by dehydration of serines and threonines, respectively. Although these residues have a suspected role in protein cross-linking and aggregation, their direct implication has yet to be determined. Here, we have taken advantage of the ability of the enteropathogen Shigella to convert the phosphothreonine residue of the pT-X-pY consensus sequence of ERK and p38 into Dhb and followed the impact of dehydration on the fate of the two MAPKs. To that end, we have generated the first antibodies recognizing Dhb-modified proteins and allowing tracing them as they form. We showed that Dhb modifications accumulate in a long-lasting manner in Shigella-infected cells, causing subsequent formation of covalent cross-links of MAPKs. Moreover, the Dhb signal correlates precisely with the activation of the Shigella type III secretion apparatus, thus evidencing injectisome activity. This observation is the first to document a causal link between Dhb formation and protein cross-linking in live cells. Detection of eliminylation is a new avenue to phosphoproteome regulation in eukaryotes that will be instrumental for the development of type III secretion inhibitors.