Impeded protein folding and function in active inflammatory bowel disease

Abstract

The intestinal tract is covered by a total of 300 square metres of IECs (intestinal epithelial cells) that covers the entire intestinal mucosa. For protection against luminal xenobiotics, pathogens and commensal microbes, these IECs are equipped with membrane-bound transporters as well as the ability to secrete specific protective proteins. In patients with active IBD (inflammatory bowel disease), the expression of these proteins, e.g. ABC (ATP-binding cassette) transporters such as ABCG2 (ABC transporter G2) and defensins, is decreased, thereby limiting the protection against various luminal threats. Correct ER (endoplasmic reticulum)-dependent protein folding is essential for the localization and function of secreted and membrane-bound proteins. Inflammatory triggers, such as cytokines and nitric oxide, can impede protein folding, which causes the accumulation of unfolded proteins inside the ER. As a result, the unfolded protein response is activated which can lead to a cellular process named ER stress. The protein folding impairment affects the function and localization of several proteins, including those involved in protection against xenobiotics. In the present review, we discuss the possible inflammatory pathways affecting protein folding and eventually leading to IEC malfunction in patients with active IBD.

Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn's disease

“…In the current study we show the occurrence of ER stress in Paneth cells in a subset of the patients and healthy controls carrying an ATG16L1 risk allele (G), using a previously described sustainable method 11. Our ER-stressed Paneth cell finding was not linked to SNPs in other possible ER stress-associated genes such as XBP1, NOD2 and IRGM, nor to active inflammation-induced ER stress 11 26 27. Therefore we hypothesised that the ER stress observed in Paneth cells results from a hampered recovery from stress or the increased demand for (antimicrobial) proteins downstream of NF-κB activation 20 28.…”

Profiles of microRNA networks in intestinal epithelial cells in a mouse model of colitis

“…Next we analyzed the target genes that were down-regulated in inflamed large-IECs and the miRNAs whose expression was up-regulated; the expression levels of these miRNAs were validated through quantitative PCR analysis ( Supplementary Figures 6a and 7b ). The target genes of interest in this analysis ( Table 4 ) that were related to IBD include ABCG2 35 , AQP8 36 , and SELENBP1 37 ; those involved in other inflammatory processes include CAR4 38 , CPN1 39 , UNC5B 40 , SCIN 41 , STIM1 42 , and HMMR 43 . The cancer-related genes are RNASEL 44 , DPEP1 45 , MLL3 46 , CDCP1 47 , and KRT20 48 ; those involved in gut homeostasis or immunity are TMIGD1 15 , ARFRP1 16 , and SEPP1 49 .…”

Fizzy: feature subset selection for metagenomics

“…The top Pfams that maximize the mutual information for the MetaHit data set are shown in Table 5 . It is known in IBD patients, the expression of ABC transporter protein (PF00005, the first feature MIM selected for classifying IBD vs. no IBD samples) is decreased which limits the protection against various luminal threats [ 26 ]. The feature selection for IBD also identified glycosyl transferase (PF00535), whose alternation is hypothesized to result in recruitment of bacteria to the gut mucosa and increased inflammation [ 27 , 28 ], and the genotype of acetyltransferase (PF00583) plays an important role in the pathogenesis of IBD, which is useful in the diagnostics and treatment of IBD [ 29 ].…”