Goblet cells need some stress

Johansson, Malin; Hansson, Gunnar C.

doi:10.1172/jci162030

Cited by 11 publications

(10 citation statements)

References 19 publications

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“…Interestingly, high levels of weakly charged MUC5B glycoforms have also been observed in asthma and in chronic obstructive pulmonary disease (COPD), and in healthy smokers who have an acquired CFTR deficiency, suggesting that CFTR dysfunction may be a common feature of obstructive airway diseases 1,34,38 with genetic or environmental origins 39 . Our study suggests that therapeutic approaches that reduce molecular crowding by alleviating ER stress through reduced protein misfolding or protein synthesis and/or enhancing degradation of the unfolded proteins may improve mucus properties 29,40 . Reducing the rate of protein synthesis also improves the folding of deltaF508-CFTR 41,42 .…”

Section: Discussionmentioning

confidence: 88%

“…Further, crowding may begin in the ER due to the accumulation of unfolded proteins, leading to ER stress and triggering the unfolded protein response (UPR) to maintain proteostasis. Mucus-secreting cells are particularly sensitive to ER stress due to the enormous size of mucin macromolecules they produce 29 . Any additional demand for protein synthesis, even in the absence of infection/inflammation may overwhelm the quality control system in vulnerable cells, allowing the misfolded proteins, such as mutated CFTR, to escape ER associated degradation (ERAD) and accumulate in the protein secretory pathway.…”

Section: Discussionmentioning

confidence: 99%

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Nano-scale viscometry reveals an inherent mucus defect in cystic fibrosis

Ponomarchuk,

Boudreault,

Gryczynski

et al. 2024

Preprint

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Abnormally viscous and thick mucus is a hallmark of cystic fibrosis (CF). How the genetic defect causes abnormal mucus in CF remains unanswered and a question of paramount interest. Mucus is produced by hydration of gel-forming mucin macromolecules that are stored in secretory granules prior to release. Current understanding of mucin/mucus structure before and after secretion remains limited and contradictory models exist. Here we used a molecular viscometer and fluorescence lifetime imaging of primary epithelial cells (Normal and CF) to measure nanometer-scale viscosity. We found significantly elevated intraluminal nanoviscosity in a population of CF mucin granules, indicating an intrinsic, pre-secretory, mucin defect. Validation experiments showed that high nanoviscosity in cellular environments is mainly due to the low mobility of water that hydrates macromolecules. Nanoviscosity influences protein conformational dynamics and function. Its elevation along the protein secretory pathway indicates molecular overcrowding and is expected to alter mucins post-translational processing, hydration, and mucus rheology after release. The nanoviscosity of extracellular CF mucus was elevated compared to non-CF mucus. Remarkably, it was higher after secretion than in granules, which suggests mucins have a weakly-ordered state in granules and adopt a highly-ordered, nematic crystalline structure extracellularly. This challenges the classical view of mucus as a porous agarose-like gel and suggests an alternative model for mucin organization before and after secretion. Our study also suggests that endoplasmic reticulum stress due to molecular overcrowding contributes to mucus pathogenesis in CF cells. It encourages the development of therapeutics that target pre-secretory mechanisms in CF and other muco-obstructive lung diseases.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Nano-scale viscometry reveals an inherent mucus defect in cystic fibrosis

Ponomarchuk,

Boudreault,

Gryczynski

et al. 2024

Preprint

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show abstract

“…Goblet cells are another class of specialized epithelial cells found in the intestinal epithelium, that secrete mucus proteins to form a mucosal layer [36,38]. This mucosal layer acts as a physical barrier to protect the host from external pathogens [59]. In contrast to mammals, who have a more developed adaptive immunity, innate immunity plays a greater role in sh [60].…”

Section: Discussionmentioning

confidence: 99%

The Impact of Chronic Antibiotics Exposure on the Gut Microbiome Dysbiosis and Mucosal Barrier-Related Pathogen Susceptibility in Zebrafish Model

Yang,

Park,

Lee

et al. 2023

Preprint

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The symbiotic community of microorganisms in the gut plays an important role in the health of the host. While many previous studies have been performed on the interaction between the gut microbiome and the host in mammals, studies in fish are still lacking. In this study, we investigated changes in the intestinal microbiome and pathogen susceptibility of zebrafish (Danio rerio) following chronic antibiotics exposure. The chronic antibiotics exposure assay was performed on zebrafish for 30 days using oxytetracycline (Otc), sulfamethoxazole/trimethoprim (Smx/Tmp), and erythromycin (Ery), which are antibiotics widely used in aquaculture industry. The microbiome analysis indicated that Fusobacteria, Proteobacteria, Firmicutes, and Bacteroidetes were the dominant phyla in the gut microbiome of zebrafish used in this study. However, in Smx/Tmp-treated zebrafish, the composition of Fusobacteria and Proteobacteria were changed significantly, and in Ery-treated zebrafish, the composition of Proteobacteria and Firmicutes were altered significantly. Although alpha diversity analysis showed that there was no significant difference in the richness, beta diversity analysis revealed a community imbalance in the gut microbiome of all chronically antibiotics exposed zebrafish. Intriguingly, in zebrafish with dysbiosis on the gut microbiome, the pathogen susceptibility to Edwardsiella piscicida, a representative Gram-negative fish pathogen, was reduced. Due to the further effect of gut microbiome dysbiosis, the number of goblet cells in the intestinal tissue was increased, and the intestinal mucosal barrier-related genes expression was also upregulated. In addition, as the innate immunity was enhanced by the increased mucosal barrier, the immune, stress-related gene expression in the intestinal tissue was downregulated. In this study, we provide new insight into the effect of gut microbiome dysbiosis on pathogen susceptibility.

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“…The creation of a mucus barrier is a crucial defense that the gastrointestinal epithelium employs to prevent bacterial entry. MUC2, a highly glycosylated gel-forming mucin, is generated in the intestine by goblet cells and forms a multilayered matrix of the mucus barrier ( Al-Shaibi et al., 2021 ; Johansson and Hansson, 2022 ). MUC2 is a key component of the mucosal layer that covers the surface of gastrointestinal epithelial cells and is the initial line of defense against both symbiotic and pathogenic bacteria ( Ye et al., 2021 ).…”

Section: Agr2 Has the Potential To Function As A Critical Regulator I...mentioning

confidence: 99%

New insights into the unfolded protein response (UPR)-anterior gradient 2 (AGR2) pathway in the regulation of intestinal barrier function in weaned piglets

Zhang,

Chen,

Liu

et al. 2023

Animal Nutrition

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Goblet cells need some stress

Cited by 11 publications

References 19 publications

Nano-scale viscometry reveals an inherent mucus defect in cystic fibrosis

Nano-scale viscometry reveals an inherent mucus defect in cystic fibrosis

The Impact of Chronic Antibiotics Exposure on the Gut Microbiome Dysbiosis and Mucosal Barrier-Related Pathogen Susceptibility in Zebrafish Model

New insights into the unfolded protein response (UPR)-anterior gradient 2 (AGR2) pathway in the regulation of intestinal barrier function in weaned piglets

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