Lead exposure disturbs ATP7B-mediated copper export from brain barrier cells by inhibiting XIAP-regulated COMMD1 protein degradation.

The brain barrier is an important structure for metal ion homeostasis. According to studies, lead (Pb) exposure disrupts the transportation of copper (Cu) through the brain barrier, which may cause impairment of the nervous system; however, the specific mechanism is unknown. The previous studies suggested the X-linked inhibitor of apoptosis (XIAP) is a sensor for cellular Cu level which mediate the degradation of the MURR1 domain-containing 1 (COMMD1) protein. XIAP/COMMD1 axis was thought to be an important regulator in Cu metabolism maintenance. In this study, the role of XIAP-regulated COMMD1 protein degradation in Pb-induced Cu disorders in brain barrier cells was investigated. Pb exposure significantly increased Cu levels in both cell types, according to atomic absorption technology testing. Western blotting and reverse transcription PCR (RT-PCR) showed that COMMD1 protein levels were significantly increased, whereas XIAP, ATP7A, and ATP7B protein levels were significantly decreased. However, there were no significant effects at the messenger RNA (mRNA) level (XIAP, ATP7A, and ATP7B). Pb-induced Cu accumulation and ATP7B expression were reduced when COMMD1 was knocked down by transient small interfering RNA (siRNA) transfection. In addition, transient plasmid transfection of XIAP before Pb exposure reduced Pb-induced Cu accumulation, increased COMMD1 protein levels, and decreased ATP7B levels. In conclusion, Pb exposure can reduce XIAP protein expression, increase COMMD1 protein levels, and specifically decrease ATP7B protein levels, resulting in Cu accumulation in brain barrier cells.

Disruption of COMMD1 accelerates diabetic atherosclerosis by promoting glycolysis.

AIMS: Diabetes will lead to serious complications, of which atherosclerosis is the most dangerous. This study aimed to explore the mechanisms of diabetic atherosclerosis. METHODS: ApoE-/- mice were fed with an high-fat diet diet and injected with streptozotocin to establish an in vivo diabetic atherosclerotic model. RAW 264.7 cells were treated with oxidized low-density lipoprotein particles (ox-LDL) and high glucose to produce an in vitro diabetic atherosclerotic model. RESULTS: In this study, we showed that diabetes promoted the progression of atherosclerosis in ApoE-/- mice and that high glucose potentiates macrophage proinflammatory activation and foam cell formation. Mechanistically, Copper metabolism MURR1 domain-containing 1(COMMD1) deficiency increased proinflammatory activation and foam cell formation, characterized by increased glycolysis, and then accelerated the process of atherosclerosis. Furthermore, 2-Deoxy-D-glucose (2-DG) reversed this effect. CONCLUSION: Taken together, we provided evidence that the lack of COMMD1 accelerates diabetic atherosclerosis via mediating the metabolic reprogramming of macrophages. Our study provides evidence of a protective role for COMMD1 and establishes COMMD1 as a potential therapeutic strategy in patients with diabetic atherosclerosis.

ERRα Attenuates Vascular Inflammation via Enhanced NFκB Degradation Pathway.

We have previously reported that ß-aminoisobutyric acid (BAIBA), a muscle-derived exercise mimetic, had anti-inflammatory and reactive oxygen species (ROS) scavenging effects in vascular endothelial cells through the enhanced expression of peroxisome proliferator-activated receptor gamma coactivator-1ß (PGC-1ß). Although BAIBA also increased the expression of estrogen-related receptor α (ERRα), the roles of ERRα in vascular endothelial cells have yet to be fully elucidated. Here, we found that human aortic endothelial cells (HAECs) infected with ERRα-expressing adenovirus had significantly decreased mRNA levels of tumor necrosis factor α-stimulated proinflammatory molecules. However, ERRα overexpression had little effect on the mRNA levels of PGC-1ß, peroxisome proliferator-activated receptors, and almost all ROS scavenging molecules, except for superoxide dismutase 2. ERRα expression significantly decreased NFκB reporter activities in a dose-dependent manner with unaltered IκBα phosphorylation levels but with a significant increase in the mRNA levels of PDZ and LIM domain protein 2 (PDLIM2) and copper metabolism gene MURR1 domain-containing protein (COMMD1), which enhance the ubiquitination and degradation of NFκB. Also, PDLIM2 and COMMD1 mRNA levels were upregulated in BAIBA-treated HAECs. Finally, we identified the ERRα-response element in the COMMD1 promoter region (-283 to -29 bp). These results indicated that ERRα exerted anti-inflammatory effects in vascular endothelial cells through COMMD1-mediated attenuation of NFκB activity, which could be an atheroprotective mechanism of physical exercise.

The NF-κB Nucleolar Stress Response Pathway.

The nuclear organelle, the nucleolus, plays a critical role in stress response and the regulation of cellular homeostasis. P53 as a downstream effector of nucleolar stress is well defined. However, new data suggests that NF-κB also acts downstream of nucleolar stress to regulate cell growth and death. In this review, we will provide insight into the NF-κB nucleolar stress response pathway. We will discuss apoptosis mediated by nucleolar sequestration of RelA and new data demonstrating a role for p62 (sequestosome (SQSTM1)) in this process. We will also discuss activation of NF-κB signalling by degradation of the RNA polymerase I (PolI) complex component, transcription initiation factor-IA (TIF-IA (RRN3)), and contexts where TIF-IA-NF-κB signalling may be important. Finally, we will discuss how this pathway is targeted by aspirin to mediate apoptosis of colon cancer cells.

A first-in-class, first-in-human, phase I trial of CIGB-552, a synthetic peptide targeting COMMD1 to inhibit the oncogenic activity of NF-κB in patients with advanced solid tumors.

CIGB-552 is a synthetic peptide that interacts with COMMD1 and upregulates its protein levels. The objectives of this phase I study were safety, pharmacokinetic profile, evaluation of the lymphocytes CD4+ and CD8+ and preliminary activity in patients with advanced tumors. A 3 + 3 dose-escalation design with seven dose levels was implemented. Patients were included until a grade 3 related adverse event occurred and the maximum tolerated dose was reached. The patients received subcutaneous administration of CIGB-552 three times per week for 2 weeks. Single-dose plasma pharmacokinetics was characterized at two dose levels, and tumor responses were classified by RECIST 1.1. Twenty-four patients received CIGB-552. Dose-limiting toxicity was associated with a transient grade 3 pruritic maculopapular rash at a dose of 7.0 mg. The maximum tolerated dose was defined as 4.7 mg. Ten patients were assessable for immunological status. Seven patients had significant changes in the ratio CD4/CD8 in response to CIGB-552 treatment; three patients did not modify the immunological status. Stable disease was observed in five patients, including two metastatic soft sarcomas. We conclude that CIGB-552 at dose 4.7 mg was well tolerated with no significant adverse events and appeared to provide some clinical benefits.

Cardiomyocyte-Specific COMMD1 Deletion Suppresses Ischemia-Induced Myocardial Apoptosis.

Copper metabolism MURR domain 1 (COMMD1) increases in ischemic myocardium along with suppressed contractility. Cardiomyocyte-specific deletion of COMMD1 preserved myocardial contractile function in response to the same ischemic insult. This study was undertaken to test the hypothesis that cardiomyocyte protection in COMMD1 myocardium is responsible for the functional preservation of the heart in response to ischemic insult. After ischemic insult, there were significantly more cardiomyocytes in the cardiomyocyte-specific COMMD1 deletion myocardium than that in WT controls. This preservation of cardiomyocytes was paralleled by a significant suppression of apoptosis in the COMMD1 deletion myocardium compared to controls. In searching for the mechanistic understanding of the anti-apoptotic effect of COMMD1 deletion, we found the anti-apoptotic Bcl-2 mRNA and protein expression were upregulated and the pro-apoptotic Bax mRNA and protein expression were downregulated. The critical transcription factor RelA, maintaining a high ratio between Bcl-2 and Bax for anti-apoptotic action, was suppressed by ischemia, but was rescued in the COMMD1 deletion myocardium. Because COMMD1 is critically involved in RelA ubiquitination and degradation, the data obtained here demonstrate that COMMD1 deletion leads to RelA preservation in ischemic myocardium, promoting the Bcl-2 anti-apoptotic pathway and suppressing the Bax pro-apoptotic pathway, and in combination, leading to protection of cardiomyocytes from ischemia-induced apoptosis.

Copper-associated hepatitis in a young Dalmatian dog in Japan.

A male 25-month-old Dalmatian dog attended our veterinary hospital because of anorexia and high circulating liver enzyme activities. Abdominal computed tomography showed a slightly small liver with rounded edges, and laparoscopic examination showed that the liver was yellowish. Histopathological examination revealed multifocal necrosis of hepatocytes and severe chronic hepatitis. Rhodanine staining showed severe copper accumulation in hepatocytes and a quantitative analysis of the copper content of the liver showed substantial accumulation (10.3 mg/g dry mass), suggesting a diagnosis of copper-associated hepatitis. Previously reported canine mutation in the COMMD1, the gene responsible for the copper-associated hepatitis in the Bedlington terrier, was not identified. To our knowledge, this is the first report of copper-associated hepatitis in a Dalmatian in Japan.

COMMD1 Exemplifies the Power of Inbred Dogs to Dissect Genetic Causes of Rare Copper-Related Disorders.

Wilson's Disease is a rare autosomal recessive disorder in humans, often presenting with hepatic copper overload. Finding the genetic cause of a rare disease, especially if it is related to food constituents like the trace element copper, is a Herculean task. This review describes examples of how the unique population structure of in-bred dog strains led to the discovery of a novel gene and two modifier genes involved in inherited copper toxicosis. COMMD1, after the discovery in 2002, was shown to be a highly promiscuous protein involved in copper transport, protein trafficking/degradation, regulation of virus replication, and inflammation. Mutations in the ATP7A and ATP7B proteins in Labrador retrievers and Dobermann dogs resulted in a wide variation in hepatic copper levels in these breeds. To our knowledge, numerous dog breeds with inherited copper toxicosis of unknown genetic origin exist. Therefore, the possibility that men's best friend will provide new leads in rare copper storage diseases seems realistic.

Phosphorylation regulates cullin-based ubiquitination in tumorigenesis.

Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors. This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination, and most importantly its influence on tumorigenesis, to provide new directions and strategies for tumor therapy.

COMMD1 upregulation is involved in copper efflux from ischemic hearts.

Copper depletion is associated with myocardial ischemic infarction, in which copper metabolism MURR domain 1 (COMMD1) is increased. The present study was undertaken to test the hypothesis that the elevated COMMD1 is responsible for copper loss from the ischemic myocardium, thus worsening myocardial ischemic injury. Mice (C57BL/6J) were subjected to left anterior descending coronary artery permanent ligation to induce myocardial ischemic infarction. In the ischemic myocardium, copper reduction was associated with a significant increase in the protein level of COMMD1. A tamoxifen-inducible, cardiomyocyte -specific Commd1 knockout mouse (C57BL/6J) model (COMMD1CMC▲/▲) was generated using the Cre-LoxP recombination system. COMMD1CMC▲/▲ and wild-type littermates were subjected to the same permanent ligation of left anterior descending coronary artery. At the 7th day after ischemic insult, COMMD1 deficiency suppressed copper loss in the heart, along with preservation of vascular endothelial growth factor and vascular endothelial growth factor receptor 1 expression and the integrity of the vascular system in the ischemic myocardium. Corresponding to this change, infarct size of ischemic heart was reduced and myocardial contractile function was well preserved in COMMD1CMC▲/▲ mice. These results thus demonstrate that upregulation of COMMD1 is at least partially responsible for copper efflux from the ischemic heart. Cardiomyocyte-specific deletion of COMMD1 helps preserve the availability of copper for angiogenesis, thus suppressing myocardial ischemic dysfunction.

COMMD1, from the Repair of DNA Double Strand Breaks, to a Novel Anti-Cancer Therapeutic Target.

Lung cancer has the highest incidence and mortality among all cancers, with non-small cell lung cancer (NSCLC) accounting for 85-90% of all lung cancers. Here we investigated the function of COMMD1 in the repair of DNA double strand breaks (DSBs) and as a prognostic and therapeutic target in NSCLC. COMMD1 function in DSB repair was investigated using reporter assays in COMMD1-siRNA-depleted cells. The role of COMMD1 in NSCLC was investigated using bioinformatic analysis, qRT-PCR and immunoblotting of control and NSCLC cells, tissue microarrays, cell viability and cell cycle experiments. DNA repair assays demonstrated that COMMD1 is required for the efficient repair of DSBs and reporter assays showed that COMMD1 functions in both non-homologous-end-joining and homologous recombination. Bioinformatic analysis showed that COMMD1 is upregulated in NSCLC, with high levels of COMMD1 associated with poor patient prognosis. COMMD1 mRNA and protein were upregulated across a panel of NSCLC cell lines and siRNA-mediated depletion of COMMD1 decreased cell proliferation and reduced cell viability of NSCLC, with enhanced death after exposure to DNA damaging-agents. Bioinformatic analyses demonstrated that COMMD1 levels positively correlate with the gene ontology DNA repair gene set enrichment signature in NSCLC. Taken together, COMMD1 functions in DSB repair, is a prognostic maker in NSCLC and is potentially a novel anti-cancer therapeutic target for NSCLC.

COMMD1, a multi-potent intracellular protein involved in copper homeostasis, protein trafficking, inflammation, and cancer.

Copper is a trace element indispensable for life, but at the same time it is implicated in reactive oxygen species formation. Several inherited copper storage diseases are described of which Wilson disease (copper overload, mutations in ATP7B gene) and Menkes disease (copper deficiency, mutations in ATP7A gene) are the most prominent ones. After the discovery in 2002 of a novel gene product (i.e. COMMD1) involved in hepatic copper handling in Bedlington terriers, studies on the mechanism of action of COMMD1 revealed numerous non-copper related functions. Effects on hepatic copper handling are likely mediated via interactions with ATP7B. In addition, COMMD1 has many more interacting partners which guide their routing to either the plasma membrane or, often in an ubiquitination-dependent fashion, trigger their proteolysis via the S26 proteasome. By stimulating NF-κB ubiquitination, COMMD1 dampens an inflammatory reaction. Finally, targeting COMMD1 function can be a novel approach in the treatment of tumors.

Long non-coding RNA SNHG5 suppresses the development of acute respiratory distress syndrome by targeting miR-205/COMMD1 axis.

Previous studies have reported the important roles of long non-coding RNAs (lncRNAs) in acute respiratory distress syndrome (ARDS). Here, we focus on the role and regulatory mechanism of lncRNA SNHG5 in ARDS. LPS was used to induce mice to establish ARDS model in vivo and to induce A549 cells to establish ARDS model in vitro. qRT-PCR was performed to determine the expressions of SNHG5, miR-205, and inflammatory cytokines. MTT assay was applied to detect cell viability. Dual-luciferase reporter (DLR) assay was performed to test the interactions among SNHG5, miR-205 and COMMD1. Western blot was used to detect the protein expression of COMMD1. Lung injury was evaluated by evaluating the score of lung injury, lung wet/dry weight ratio, and myeloperoxidase (MPO) activity. SNHG5 was downregulated, while miR-205 was upregulated in the serum of ARDS patients and lung tissues of LPS-induced mice. Upregulation of SNHG5 or down-regulation of miR-205 inhibited inflammation and promoted the viability of LPS-induced A549 cells. SNHG5 alleviated the lung injury of ARDS mice. MiR-205 was a target of SNHG5 and inversely correlated with SNHG5. COMMD1 was targeted by miR-205, and was positively regulated by SNHG5. MiR-205 mimics or sh-COMMD1 reversed the promoting effect of SNHG5 on cell viability and the suppressing effect of SNHG5 on inflammation in cellular model of ARDS. Meantime, miR-205 mimics reversed the relieving effect of SNHG5 on lung injury in mouse model of ARDS. SNHG5 acted as a sponge for miR-205 to ameliorate LPS-induced ARDS by regulating COMMD1.

Behavioral Effects of Neuronal, Parent-specific Commd1 Knockout in Mice.

In this study we focused on gene expression and behavioral differences in mice with brain-specific Commd1 knockout. Commd1 is an imprinted gene with preferential maternal expression, residing within a larger genomic region previously found to affect sensorimotor gating. In this study, individuals harboring a conditional Commd1 mutant allele were bred with Syn1-Cre animals, paying special attention to the parent of origin of the Commd1 mutation. Analysis of mRNA levels of Commd1 and phenotypic tests, including the open field, sensorimotor gating, and the forced swim test, were conducted on offspring with either maternally or paternally derived Commd1 knockout. We found that measurable Commd1 mRNA knockout occurred only in the maternally derived line and affected stereotypy and depressive-like behavior without differences in total locomotion compared to controls. Interestingly, we found that maternal knockout animals exhibited decreased time swimming and increased time immobile when compared to maternal and paternal wild type, and paternal knockout animals. However, there were no differences in climbing behavior between genotypes. This study demonstrates an in vivo behavioral role for Commd1 for the first time and demonstrates the need for careful interpretation of experimental results involving Cre-based knockout systems.

The Anticancer Peptide CIGB-552 Exerts Anti-Inflammatory and Anti-Angiogenic Effects through COMMD1.

CIGB-552 is a synthetic anti-tumor peptide capable of reducing tumor size and increasing the lifespan of tumor-bearing mice. Part of its anti-cancer effects consists of inducing apoptosis, modulating NF-kB signaling pathway, and the angiogenesis process. Although one of its major mediators, the COMMD1 protein, has been identified, the mechanism by which CIGB-552 exerts such effects remains elusive. In the present study, we show the role of COMMD1 in CIGB-552 mechanism of action by generating the COMMD1 knock-out from the human lung cancer cell line NCI-H460. A microarray was performed to analyze both wild-type and KO cell lines with regard to CIGB-552 treatment. Additionally, different signaling pathways were studied in both cell lines to validate the results. Furthermore, the interaction between CIGB-552 and COMMD1 was analyzed by confocal microscopy. By signaling pathway analysis we found that genes involved in cell proliferation and apoptosis, oncogenic transformation, angiogenesis and inflammatory response are potentially regulated by the treatment with CIGB-552. We then demonstrated that CIGB-552 is capable of modulating NF-kB in both 2D and 3D cell culture models. Finally, we show that the ability of CIGB-552 to negatively modulate NF-kB and HIF-1 pathways is impaired in the COMMD1 knock-out NCI-H460 cell line, confirming that COMMD1 is essential for the peptide mechanism of action.

Reduced FXR Target Gene Expression in Copper-Laden Livers of COMMD1-Deficient Dogs.

Wilson's disease (WD), an autosomal recessive disorder, results in copper accumulation in the liver as a consequence of mutations in the gene ATPase copper transporting beta (ATP7B). The disease is characterized by chronic hepatitis, eventually resulting in liver cirrhosis. Recent studies have shown that dysregulation of nuclear receptors (NR) by high hepatic copper levels is an important event in the pathogenesis of liver disease in WD. Intracellular trafficking of ATP7B is mediated by COMMD1 and, in Bedlington terriers, a mutation in the COMMD1 gene results in high hepatic copper levels. Here, we demonstrate a reduced Farnesoid X nuclear receptor (FXR)-activity in liver biopsies of COMMD1-deficient dogs with copper toxicosis, a unique large animal model of WD. FXR-induced target genes, small heterodimer partner (SHP), and apolipoprotein E (ApoE) were down-regulated in liver samples from COMMD1-deficient dogs with hepatic copper accumulation. In contrast, the relative mRNA levels of the two CYP-enzymes (reduced by FXR activity) was similar in both groups. These data are in line with the previously observed reduced FXR activity in livers of ATP7B-/- mice and WD patients. Therefore, these data further corroborate on the importance of the COMMD1-deficient dogs as a large animal model for WD.

COMMD1 and PtdIns(4,5)P2 interaction maintain ATP7B copper transporter trafficking fidelity in HepG2 cells.

Copper-responsive intracellular ATP7B trafficking is crucial for maintaining the copper balance in mammalian hepatocytes and thus copper levels in organs. The copper metabolism domain-containing protein 1 (COMMD1) binds both the ATP7B copper transporter and phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2], whereas COMMD1 loss causes hepatocyte copper accumulation. Although it is clear that COMMD1 is localized to endocytic trafficking complexes, a direct function for COMMD1 in ATP7B trafficking has not yet been defined. In this study, experiments using quantitative colocalization analysis reveal that COMMD1 modulates copper-responsive ATP7B trafficking through recruitment to PtdIns(4,5)P2 Decreased COMMD1 abundance results in loss of ATP7B from lysosomes and the trans-Golgi network (TGN) in high copper conditions, although excess expression of COMMD1 also disrupts ATP7B trafficking and TGN structure. Overexpression of COMMD1 mutated to inhibit PtdIns(4,5)P2 binding has little impact on ATP7B trafficking. A mechanistic PtdIns(4,5)P2-mediated function for COMMD1 is proposed that is consistent with decreased cellular copper export as a result of disruption of the ATP7B trafficking itinerary and early endosome accumulation when COMMD1 is depleted. PtdIns(4,5)P2 interaction with COMMD1 as well as COMMD1 abundance could both be important in maintenance of specific membrane protein trafficking pathways.

Insights into the Relationship between Nucleolar Stress and the NF-κB Pathway.

The nuclear organelle the nucleolus and the transcription factor nuclear factor of κ-light-chain-enhancer of activated B cells (NF-κB) are both central to the control of cellular homeostasis, dysregulated in common diseases and implicated in the ageing process. Until recently, it was believed that they acted independently to regulate homeostasis in health and disease. However, there is an emerging body of evidence suggesting that nucleoli and NF-κB signalling converge at multiple levels. Here we will review current understanding of this crosstalk. We will discuss activation of the NF-κB pathway by nucleolar stress and induction of apoptosis by nucleolar sequestration of NF-κB/RelA. We will also discuss the role of TIF-IA, COMMD1, and nucleophosmin, which are key players in this crosstalk, and the therapeutic relevance, particularly with respect to the antitumour effects of aspirin.

COMMD1 regulates cell proliferation and cell cycle progression by modulating p21 Cip1 levels.

Copper metabolism MURR1 domain-containing 1 (COMMD1) is a protein that participates in multiple cellular processes, including copper homeostasis and nuclear factor kappa B (NF-κB) and hypoxia-inducible factor 1α (HIF-1α) signaling. The COMMD1 upstream regulators X-linked inhibitor of apoptosis protein (XIAP) and p300 and downstream targets such as NF-κB and HIF-1α are involved in the regulation of cell proliferation and cell cycle progression. However, whether COMMD1 regulates cell proliferation and the cell cycle remains unclear. In the present study, we demonstrated that both overexpression and knockdown of COMMD1 affected the proliferation of HEK293 cells, and the cell cycle assay revealed that ectopic expression of COMMD1 arrested the cell cycle at the G1 phase. Furthermore, western blot analysis showed that COMMD1 affected p21 Cip1 levels. Taken together, these results suggest that COMMD1 regulates cell proliferation and cell cycle progression by modulating p21 Cip1 levels. Abbreviations COMMD1: Copper metabolism MURR1 domain containing 1; XIAP: X chromosome-linked inhibitor of apoptosis protein; FCS: Fetal calf serum; WCE: Whole cell extracts; RT-PCR: Reverse transcription-polymerase chain reaction; HEK293: Human embryonic kidney 293; ShRNA: Short hairpin RNA; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; ARF: Alternate reading frame protein product of the CDKN2A locus.

Microbial Sensing by Intestinal Myeloid Cells Controls Carcinogenesis and Epithelial Differentiation.

Physiologic microbe-host interactions in the intestine require the maintenance of the microbiota in a luminal compartment through a complex interplay between epithelial and immune cells. However, the roles of mucosal myeloid cells in this process remain incompletely understood. In this study, we identified that decreased myeloid cell phagocytic activity promotes colon tumorigenesis. We show that this is due to bacterial accumulation in the lamina propria and present evidence that the underlying mechanism is bacterial induction of prostaglandin production by myeloid cells. Moreover, we show that similar events in the normal colonic mucosa lead to reductions in Tuft cells, goblet cells, and the mucus barrier of the colonic epithelium. These alterations are again linked to the induction of prostaglandin production in response to bacterial penetration of the mucosa. Altogether, our work highlights immune cell-epithelial cell interactions triggered by the microbiota that control intestinal immunity, epithelial differentiation, and carcinogenesis.