Over the past two decades, our appreciation of the gut mucus has moved from a static lubricant to a dynamic and essential component of the gut ecosystem that not only mediates the interface between ...host tissues and vast microbiota, but regulates how this ecosystem functions to promote mutualistic symbioses and protect from microbe-driven diseases. By delving into the complex chemistry and biology of the mucus, combined with innovative in vivo and ex vivo approaches, recent studies have revealed novel insights into the formation and function of the mucus system, the O-glycans that make up this system, and how they mediate two major host-defense strategies - resistance and tolerance - to reduce damage caused by indigenous microbes and opportunistic pathogens. This current review summarizes these findings by highlighting the emerging roles of mucus and mucin-type O-glycans in influencing host and microbial physiology with an emphasis on host defense strategies against bacteria in the gastrointestinal tract.
Core 1-derived mucin-type O-glycans (O-glycans) are a major component of gastric mucus with an unclear role. To address this, we generated mice lacking gastric epithelial O-glycans (GEC C1galt1-/-). ...GEC C1galt1-/- mice exhibited spontaneous gastritis that progressed to adenocarcinoma with ∼80% penetrance by 1 yr. GEC C1galt1-/- gastric epithelium exhibited defective expression of a major mucus forming O-glycoprotein Muc5AC relative to WT controls, which was associated with impaired gastric acid homeostasis. Inflammation and tumorigenesis in GEC C1galt1-/- stomach were concurrent with activation of caspases 1 and 11 (Casp1/11)-dependent inflammasome. GEC C1galt1-/- mice genetically lacking Casp1/11 had reduced gastritis and gastric cancer progression. Notably, expression of Tn antigen, a truncated form of O-glycan, and CASP1 activation was associated with tumor progression in gastric cancer patients. These results reveal a critical role of O-glycosylation in gastric homeostasis and the protection of the gastric mucosa from Casp1-mediated gastric inflammation and cancer.
A strain FDN-01 was isolated from the sequencing batch biofilm reactor (SBBR) which was seeded with wasted activated sludge from a municipal wastewater treatment plant in Shanghai. Bacterium FDN-01 ...was identified as Thauera sp., and Genbank Sequence_ID was KY393097. By comparing inorganic total nitrogen (TN) removal efficiency by strain FDN-01 under different conditions, the optimal initial pH, carbon source and the ratio of carbon to nitrogen were 7.5, sodium succinate and 4.0, respectively. Inorganic TN removal efficiency was 93% within 3 d while the concentration of nitrate was 100 mg/L, and the type of substrates affected extracellular polymeric substances (EPS) production and the ratio of protein to polysaccharide in the EPS. Further investigation for the application of strain FDN-01 in the SBBRs showed that anoxic ammonia oxidation occurred at room temperature, and the removal efficiencies of inorganic TN were noticeably enhanced by the augmentation of bacterium FDN-01 back into the SBBR. This study provided a promising method of TN removal requiring less carbon source in the wastewater.
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•A newly strain FDN-01 was isolated from the sequencing batch biofilm reactor.•FDN-01 was identified as Thauera sp., and Genbank Sequence_ID was KY393097.•The removal efficiency of inorganic TN by augmentation of strain FDN-01 back into SBBRs was evidently increased.•The type of substrates affected EPS production and the ratio of protein to polysaccharide in the EPS.•A promising method of nitrogen removal from domestic sewage with lower C/N was provided.
This paper finds that compared with non-state-owned firms, Chinese state-owned enterprises controlled by province, city, and county governments (local SOEs) are more likely to hire small auditors ...within the same region (small local auditors). In regions with less developed institutions, SOEs controlled by central government (central SOEs) also have such a tendency. However, the tendency of local and central SOEs to hire small local auditors is attenuated as the institutions develop. This auditor choice pattern is likely to be explained by SOEs’ lack of demand for large or non-local auditors, small local auditors’ superior local knowledge, and SOEs’ collusion incentives.
The liver has recently been identified as a major organ for destruction of desialylated platelets. However, the underlying mechanism remains unclear. Kupffer cells, which are professional phagocytic ...cells in the liver, comprise the largest population of resident tissue macrophages in the body. Kupffer cells express a C-type lectin receptor, CLEC4F, that recognizes desialylated glycans with an unclear in vivo role in mediating platelet destruction. In this study, we generated a CLEC4F-deficient mouse model (Clec4f
) and found that CLEC4F was specifically expressed by Kupffer cells. Using the Clec4f
mice and a newly generated platelet-specific reporter mouse line, we revealed a critical role for CLEC4F on Kupffer cells in mediating destruction of desialylated platelets in the liver in vivo. Platelet clearance experiments and ultrastructural analysis revealed that desialylated platelets were phagocytized predominantly by Kupffer cells in a CLEC4F-dependent manner in mice. Collectively, these findings identify CLEC4F as a Kupffer cell receptor important for the destruction of desialylated platelets induced by bacteria-derived neuraminidases, which provide new insights into the pathogenesis of thrombocytopenia in disease conditions such as sepsis.
Colon mucus segregates the intestinal microbiota from host tissues, but how it organizes to function throughout the colon is unclear. In mice, we found that colon mucus consists of two distinct ...O-glycosylated entities of Muc2: a major form produced by the proximal colon, which encapsulates the fecal material including the microbiota, and a minor form derived from the distal colon, which adheres to the major form. The microbiota directs its own encapsulation by inducing Muc2 production from proximal colon goblet cells. In turn, O-glycans on proximal colon-derived Muc2 modulate the structure and function of the microbiota as well as transcription in the colon mucosa. Our work shows how proximal colon control of mucin production is an important element in the regulation of host-microbiota symbiosis.
Mannose-6-phosphate (M6P) is a posttranslational modification on N-linked glycans on lysosomal hydrolases in the Golgi apparatus, which is required for selective transport of lysosomal hydrolases ...from the Golgi apparatus to lysosomes via M6P receptors. Defects in M6P modification by genetic manipulations or in hereditary genetic disorders result in abnormal extracellular secretion of lysosomal hydrolases and are thus the basis of the pathogenesis of lysosome storage diseases. N-acetylglucosamine (GlcNAc)-1-phosphotransferase, an enzyme catalyzing M6P modification, is synthesized as an inert form that requires proteolytic activation by the Golgi-localized protease, site-1 protease (S1P). S1P, encoded by membrane-bound transcription factor peptidase, site 1 (MBTPS1), is ubiquitously expressed and functions sequentially with the site-2 protease to proteolytically activate unique membrane-bound latent transcription factors in the Golgi apparatus. These transcription factors include sterol regulatory element-binding protein required for inducing lipogenesis, and activating transcription factor 6 required for inducing endoplasmic reticulum stress-related unfolded protein response. Since we reported the first patient with MBTPS1 pathogenic variants who has congenital skeletal dysplasia due to compound endoplasmic reticulum and lysosomal dysfunctions, there have been a few reports regarding novel MBTPS1 variants worldwide. Here we overview genotype-phenotype relationships in so far reported patients with MBTPS1 variants.
Most platelet membrane proteins are modified by mucin-type core 1-derived glycans (O-glycans). However, the biological importance of O-glycans in platelet clearance is unclear. Here, we generated ...mice with a hematopoietic cell-specific loss of O-glycans (HC C1galt1
−/−). These mice lack O-glycans on platelets and exhibit reduced peripheral platelet numbers. Platelets from HC C1galt1
−/− mice show reduced levels of α-2,3-linked sialic acids and increased accumulation in the liver relative to wild-type platelets. The preferential accumulation of HC C1galt1
−/− platelets in the liver was reduced in mice lacking the hepatic asialoglycoprotein receptor Ashwell–Morell receptor (AMR). However, we found that Kupffer cells are the primary cells phagocytosing HC C1galt1
−/− platelets in the liver. Our results demonstrate that hepatic AMR promotes preferential adherence to and phagocytosis of desialylated and/or HC C1galt1
−/− platelets by the Kupffer cell through its C-type lectin receptor CLEC4F. These findings provide insights into an essential role for core 1 O-glycosylation of platelets in their clearance in the liver.
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