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IL-22 induces IL-18 expression by intestinal epithelial cells. Authors show here that IL-18 is a key barrier maintenance factor during adherent-invasive E. coli invasion, inducing expression of anti-microbial genes in Paneth cells via Stat3, prompting IFNγ expression in T cells and triggering intestinal Lgr5+ stem cell expansion via Tcf4.

Galectins are carbohydrate binding proteins previously implicated in sensing and repairing damaged lysosomes. Here, the authors show that galectin-9 has specific lysosomal roles in autophagy and contributes to cell degeneration and apoptosis in colitis and pancreatitis in mice.

In gut epithelium, IL-22 transmits signals through STAT3 phosphorylation (pSTAT3) which provides intestinal immunity. Many components in the IL-22-pSTAT3 pathway have been identified as risk factors for inflammatory bowel disease (IBD) and some of them are considered as promising therapeutic targets. However, new perspectives are still needed to understand IL-22-pSTAT3 signaling for effective clinical interventions in IBD patients. Here, we revealed activating transcription factor 3 (ATF3), recently identified to be upregulated in patients with active IBD, as a crucial player in the epithelial IL-22-pSTAT3 signaling cascade. We found ATF3 is central to intestinal homeostasis and provides protection during colitis. Loss of ATF3 led to decreased crypt numbers, more shortened colon length, impaired ileal fucosylation at the steady state, and lethal disease activity during DSS-induced colitis which can be effectively ameliorated by rectal transplantation of wild-type colonic organoids. Epithelial stem cells and Paneth cells form a niche to orchestrate epithelial regeneration and host-microbe interactions, and IL-22-pSTAT3 signaling is a key guardian for this niche. We found ATF3 is critical for niche maintenance as ATF3 deficiency caused compromised stem cell growth and regeneration, as well as Paneth cell degeneration and loss of anti-microbial peptide (AMP)-producing granules, indicative of malfunction of Paneth/stem cell network. Mechanistically, we found IL-22 upregulates ATF3, which is required to relay IL-22 signaling leading to STAT3 phosphorylation and subsequent AMP induction. Intriguingly, ATF3 itself does not act on STAT3 directly, instead ATF3 regulates pSTAT3 by negatively targeting protein tyrosine phosphatases (PTPs) including SHP2 and PTP-Meg2. Furthermore, we identified ATF3 is also involved in IL-6-mediated STAT3 activation in T cells and loss of ATF3 leads to reduced capacity of Th17 cells to produce their signature cytokine IL-22 and IL-17A. Collectively, our results suggest that via IL-22-pSTAT3 signaling in the epithelium and IL-6-pSTAT3 signaling in Th17 cells, ATF3 mediates a cross-regulation in the barrier to maintain mucosal homeostasis and immunity.

Inhibiting proteasome functional insufficiency plays an essential role in cancer prevention. Alternative strategies to target ubiquitin enzymes and ubiquitin-signal autophagic degradation can be the potential treatments. Phenolic compounds demonstrated anti-cancer effects. Phenolic compounds not only effectively inhibit E1, deubiquitinating enzyme, and 26S activity but also induce apoptosis in A549 cells. The IC50 of 26S activity and LD50 of A549 cells were nearly equivalent. Therefore, apoptosis may occur via the inhibition of the 26S proteasome activity. Inhibition of the proteasome by tannic acid in A549 cells resulted in reduction of S5a and 20S, accumulation of ubiquitin, and degradation of PARP, followed by induction of apoptosis. USP15 may play an essential role in the stability and activity of caspase-3. The levels of S5a, USP15 and USP47 were regulated by phenolic compounds, and the levels of procaspase-3 and polyADP-ribose polymerase were also decreased in A549 cells treated with phenolic compounds. Interestingly, tannic acid decreased Ub-conjugates while M + G + E increased the accumulation of Ub-conjugates in A549 reporter cells, whereas ubiquitin, E1, and USP47 levels were low in M + G + E-treated A549 reporter cells at 24 hours. Taken together, phenolic compounds may play an important role in mediating apoptosis by regulating the ubiquitin–proteasome pathway and autophagy system.