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The deubiquitinase OTUD4 inhibits the expression of antimicrobial peptides in Paneth cells to support intestinal inflammation and bacterial infection

ABSTRACT: The deubiquitinase OTUD4 inhibits the expression of antimicrobial peptides in Paneth cells to support intestinal inflammation and bacterial infection

PROVIDER: PRJNA923635 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23073736_1.fastq.gz	Fastqsanger.gz
	SRR23073736_2.fastq.gz	Fastqsanger.gz
	SRR23073737_1.fastq.gz	Fastqsanger.gz
	SRR23073737_2.fastq.gz	Fastqsanger.gz
	SRR23073738_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

The deubiquitinase OTUD4 inhibits the expression of antimicrobial peptides in Paneth cells to support intestinal inflammation and bacterial infection

Project description:The intestinal epithelial barrier plays critical role in the intestinal homeostasis and dysfunction of the epithelial barrier causes microbial invasion that would lead to inflammation in the gut. Antimicrobial peptides (AMPs) are essential components of the epithelial barrier to inhibit bacterial invasion. The regulatory mechanisms of the expression of AMPs are not fully characterized. Here, we report a cell-type-specific role of ovarian tumor family deubiquitinase 4 (OTUD4) in experimental colitis and bacterial infection. OTUD4 is upregulated in the inflamed mucosa of IBD patients and in the colon of mice treated with dextran sulfate sodium salt (DSS). Knockout of OTUD4 in intestinal organoids promotes the expression of AMPs after the stimulation with lipopolysaccharide (LPS), peptidoglycan (PGN), or Salmonella typhimurium (S.t.). In addition, the expression of AMPs was upregulated in intestinal epithelial cells (IECs) after DSS treatment or S.t. infection. Consistently, Vil-Cre;Otud4fl/fl mice and Def-Cre;Otud4fl/fl mice exhibit hyper-resistance to DSS-induced colitis and S.t. infection compared to Otud4fl/fl mice. Mechanistically, Knockout of OTUD4 results in hyper K63-linked ubiquitination of MyD88 and increases the activation of the NF-κB signaling pathway and MAPK signaling pathway to promote the expression of AMPs. These finds collectively highlight an indispensable role of OTUD4 in paneth cells to modulate AMPs production, indicating OTUD4 as a promoter and potential druggable target for gastrointestinal inflammation and bacterial infection.

2023-03-01 | GSE222836 | GEO

The deubiquitinase OTUD4 inhibits the expression of antimicrobial peptides in Paneth cells to support intestinal inflammation and bacterial infection.

Project description:Dysfunction of the intestinal epithelial barrier causes microbial invasion that would lead to inflammation in the gut. Antimicrobial peptides (AMPs) are essential components of the intestinal epithelial barrier, while the regulatory mechanisms of AMPs expression are not fully characterized. Here, we report that the ovarian tumor family deubiquitinase 4 (OTUD4) in Paneth cells restricts the expression of AMPs and thereby promotes experimental colitis and bacterial infection. OTUD4 is upregulated in the inflamed mucosa of ulcerative colitis patients and in the colon of mice treated with dextran sulfate sodium salt (DSS). Knockout of OTUD4 promotes the expression of AMPs in intestinal organoids after stimulation with lipopolysaccharide (LPS) or peptidoglycan (PGN) and in the intestinal epithelial cells (IECs) of mice after DSS treatment or Salmonella typhimurium (S.t.) infection. Consistently, Vil-Cre;Otud4fl/fl mice and Def-Cre;Otud4fl/fl mice exhibit hyper-resistance to DSS-induced colitis and S.t. infection compared to Otud4fl/fl mice. Mechanistically, knockout of OTUD4 results in hyper K63-linked ubiquitination of MyD88 and increases the activation of NF-κB and MAPKs to promote the expression of AMPs. These findings collectively highlight an indispensable role of OTUD4 in Paneth cells to modulate AMPs production and indicate OTUD4 as a potential target for gastrointestinal inflammation and bacterial infection.

| S-EPMC10123543 | biostudies-literature

Peptide YY: a Paneth cell antimicrobial peptide that maintains Candida gut commensalism.

Project description:The mammalian gut secretes a family of multifunctional peptides that affect appetite, intestinal secretions, and motility, while some regulate the microbiota. We report peptide YY (PYY1-36), but not endocrine PYY3-36, is an antimicrobial peptide (AMP) expressed by gut epithelial Paneth Cells (PC). PC-PYY has limited antibacterial activity, but shows selective activity against virulent hyphal, but not yeast forms, of Candida albicans. 5 PC-PYY is a cationic molecule that interacts with the anionic surfaces of fungal hyphae to cause membrane disruption and transcriptional reprogramming to maintain the yeast phenotype of the fungus. PC-PYY is packaged into secretory granules and is secreted into and retained by surface mucus, which optimizes PC-PYY activity. Hence, PC-PYY acts as a selective antifungal AMP that contributes to the maintenance of gut fungal commensalism.

2024-02-28 | GSE229566 | GEO

Paneth cells

Project description:Paneth cells

| PRJNA994579 | ENA

Antimicrobial peptides modulate long-term memory

Project description:Antimicrobial peptides modulate long-term memory

| PRJNA450853 | ENA

RNA-seq of mouse ileum to investigate the role of IL-17 receptor signaling in Paneth cells in their biology and intestinal physiology

Project description:IL-17 receptor plays a major role in the antibacterial defense and regulation of host-microbiota interaction. However its impact on Paneth cells, cell-type specific for production of antibacterial peptides, is still not clear. Here, we used genetic depletion of IL-17 receptor specific for Paneth cell population (Defa6-iCre x Il17ra-flox) and performed the RNA sequencing on FACS-sorted Paneth cells and also complete ileum tissue, comparing Cre+ and Cre- littermates.

2022-01-01 | E-MTAB-10038 | biostudies-arrayexpress

Loss of L-cells due to acute graft-versus-host disease leads to Paneth cell defects which can be compensated by glucagon like peptide-2

Project description:Paneth cells are targets of allo-reactive T cells during acute graft-versus-host disease (GVHD). GVHD-related loss of Paneth cells is connected to intestinal dysbiosis and a decline of antimicrobial peptides. Glucagon-like-peptide-2 (GLP-2) is an enteroendocrine tissue hormone, produced by the intestinal L-cells, that leads to expansion of Paneth cells. Microarray-based analysis of the intestinal tract revealed upregulation of a host-defense gene signature, increased Reg3-γ and Defensin-α-4 in the teduglutide treated group compared to the vehicle treated group. these results indicate that treatment of GVHD mice the GLP-2 analogue, teduglutide, restores intestinal homeostasis with increased Paneth cells and antimicrobial peptides

2023-10-29 | GSE138439 | GEO

Control of Paneth cell fate, intestinal inflammation and tumorigenesis by PKCλ/ι

Project description:Paneth cells are a highly specialized population of intestinal epithelial cells located in the crypt adjacent to Lgr5+ stem cells, from which they differentiate through a process that requires downregulation of the Notch pathway. Their ability to store and release antimicrobial peptides protects the host from intestinal pathogens and controls intestinal inflammation. Here we show that PKCλ/ι is required for Paneth cell differentiation at the level of Atoh1 and Gfi1, through the control of EZH2 stability by direct phosphorylation. The selective inactivation of PKCλ/ι in epithelial cells results in the loss of mature Paneth cells, increased apoptosis and inflammation, and enhanced tumorigenesis. Importantly, PKCλ/ι expression in human Paneth cells decreases with progression of Crohn's disease. Kaplan-Meier survival analysis of CRC patients revealed that low PRKCI levels correlated with significantly worse patient survival. Therefore, PKCλ/ι is a negative regulator of intestinal inflammation and cancer through its role in Paneth cell homeostasis.

2017-08-23 | GSE84118 | GEO

Collateral sensitivity of antibiotic resistant bacteria to antimicrobial peptides

Project description:Cationic antimicrobial peptides (CAPs) are promising novel alternatives to conventional antibacterial agents, but the overlap in resistance mechanisms between small-molecule antibiotics and CAPs is unknown. Does evolution of antibiotic resistance decrease (cross-resistance) or increase (collateral sensitivity) susceptibility to CAPs? We systematically addressed this issue by studying the susceptibilities of a comprehensive set of antibiotic resistant Escherichia coli strains towards 24 antimicrobial peptides. Strikingly, antibiotic resistant bacteria frequently showed collateral sensitivity to CAPs, while cross-resistance was relatively rare. We identified clinically relevant multidrug resistance mutations that simultaneously elevate susceptibility to certain CAPs. Transcriptome and chemogenomic analysis revealed that such mutations frequently alter the lipopolysaccharide composition of the outer cell membrane and thereby increase the killing efficiency of membrane-interacting antimicrobial peptides. Furthermore, we identified CAP-antibiotic combinations that rescue the activity of existing antibiotics and slow down the evolution of resistance to antibiotics. Our work provides a proof of principle for the development of peptide based antibiotic adjuvants that enhance antibiotic action and block evolution of resistance.

2018-03-29 | GSE96706 | GEO

Proteomic profiling of mouse Paneth cells microdissected from small intestinal tissue

Project description:Paneth cells are antimicrobial peptide-secreting cells located at the base of the crypts of the small intestine. The proteome of Paneth cells is not well defined because of their co-existence with stem cells making it difficult to culture Panth cells alone in vitro. Using a simplied toluidine blue O method for staining mouse intestinal tissue, laser capture microdissection (LCM) to isolate cells from the crypt region and surfactant assisted one pot protein digestion, we identified more than 1,300 proteins from crypts equivalent to 18,000 cells. Compared with the proteomes of villi and smooth muscle regions, the crypt proteome is highly enriched in defensins, lysozymes and other antimicrobial peptides that are characteristic of Paneth cells. The sensitivity of the LCM-based proteomics approach was also assessed using a smaller number of cell equivalent tissues, a comparable proteomic coverage can be achieved with 3,600 cells. This work is the first proteomics study of intestinal tissue enriched with Paneth cells. The simplied workflow enables profiling of Paneth cell associated pathological changes at the proteome level directly from frozen intestinal tissue. It may also be useful for proteomics studies of other spatially resolved cell types from other tissues.

2022-10-12 | PXD034143 | Pride

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