A centric view of JAK/STAT5 in intestinal homeostasis, infection, and inflammation

Surbek, Marta; Tse, William Ka Fai; Moriggl, Richard; Han, Xiaonan

doi:10.1016/j.cyto.2020.155392

Cited by 18 publications

(12 citation statements)

References 103 publications

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“…2 genes as highly upregulated in neurod1 ΔUCE ( Fig 10B and S3 Table ). These two proteins are orthologous to the mammalian CUZD1, known to be a critical mediator of the JAK/STAT5 signaling pathway [ 23 ], important for intestinal homeostasis [ 24 ]. A strong upregulation of mfsd4aa (major facilitator superfamily domain-containing protein 4) (~18X) is also observed ( Fig 10B ) which was also specifically induced by the Tg7 (ΔUCE) and Tg8 (ΔECD) GOF ( Fig 6C , panel 3).…”

Section: Resultsmentioning

confidence: 99%

Identification of an evolutionarily conserved domain in Neurod1 favouring enteroendocrine versus goblet cell fate

et al. 2022

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ARP/ASCL transcription factors are key determinants of cell fate specification in a wide variety of tissues, coordinating the acquisition of generic cell fates and of specific subtype identities. How these factors, recognizing highly similar DNA motifs, display specific activities, is not yet fully understood. To address this issue, we overexpressed different ARP/ASCL factors in zebrafish ascl1a-/- mutant embryos to determine which ones are able to rescue the intestinal secretory lineage. We found that Ascl1a/b, Atoh1a/b and Neurod1 factors are all able to trigger the first step of the secretory regulatory cascade but distinct secretory cells are induced by these factors. Indeed, Neurod1 rescues the enteroendocrine lineage while Ascl1a/b and Atoh1a/b rescue the goblet cells. Gain-of-function experiments with Ascl1a/Neurod1 chimeric proteins revealed that the functional divergence is encoded by a 19-aa ultra-conserved element (UCE), present in all Neurod members but absent in the other ARP/ASCL proteins. Importantly, inserting the UCE into the Ascl1a protein reverse the rescuing capacity of this Ascl1a chimeric protein that cannot rescue the goblet cells anymore but efficiently rescue the enteroendocrine cells. This novel domain acts indeed as a goblet cell fate repressor that inhibits gfi1aa expression, known to be important for goblet cell differentiation. Deleting the UCE domain of the endogenous Neurod1 protein leads to an increase in the number of goblet cells concomitant with a reduction of the enteroendocrine cells, phenotype also observed in the neurod1 null mutant. This highlight the crucial function of the UCE domain for NeuroD1 activity in the intestine. As Gfi1 acts as a binary cell fate switch in several tissues where Neurod1 is also expressed, we can envision a similar role of the UCE in other tissues, allowing Neurod1 to repress Gfi1 to influence the balance between cell fates.

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Section: Resultsmentioning

confidence: 99%

Identification of an evolutionarily conserved domain in Neurod1 favouring enteroendocrine versus goblet cell fate

et al. 2022

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“…JAK/STAT5 signaling plays a key role in regulating the intestinal response to infection and inflammation. Modulating internal STAT5 can protect the gastrointestinal tract from injury in gastrointestinal diseases [ 31 ]. The STAT5 regulatory mechanism in mast cells is important for the pathogenesis of atopic dermatitis [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Regulatory Factors and Prognostic Markers in Amyotrophic Lateral Sclerosis

Sun

et al. 2022

Antioxidants

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of motor neurons, leading to muscle atrophy, paralysis and even death. Immune disorder, redox imbalance, autophagy disorder, and iron homeostasis disorder have been shown to play critical roles in the pathogenesis of ALS. However, the exact pathogenic genes and the underlying mechanism of ALS remain unclear. The purpose of this study was to screen for pathogenic regulatory genes and prognostic markers in ALS using bioinformatics methods. We used Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene set enrichment analysis (GSEA), and expression regulation network analysis to investigate the function of differentially expressed genes in the nerve tissue, lymphoid tissue, and whole blood of patients with ALS. Our results showed that the up-regulated genes were mainly involved in immune regulation and inflammation, and the down-regulated genes were mainly involved in energy metabolism and redox processes. Eleven up-regulated transcription factors (CEBPB, CEBPD, STAT5A, STAT6, RUNX1, REL, SMAD3, GABPB2, FOXO1, PAX6, and FOXJ1) and one down-regulated transcription factor (NOG) in the nerve tissue of patients with ALS likely play important regulatory roles in the pathogenesis of ALS. Based on construction and evaluation of the ALS biomarker screening model, cluster analysis of the identified characteristic genes, univariate Cox proportional hazards regression analysis, and the random survival forest algorithm, we found that MAEA, TPST1, IFNGR2, and ALAS2 may be prognostic markers regarding the survival of ALS patients. High expression of MAEA, TPST1, and IFNGR2 and low expression of ALAS2 in ALS patients may be closely related to short survival of ALS patients. Taken together, our results indicate that immune disorders, inflammation, energy metabolism, and redox imbalance may be the important pathogenic factors of ALS. CEBPB, CEBPD, STAT5A, STAT6, RUNX1, REL, SMAD3, GABPB2, FOXO1, PAX6, FOXJ1, and NOG may be important regulatory factors linked to the pathogenesis of ALS. MAEA, TPST1, IFNGR2, and ALAS2 are potential important ALS prognostic markers. Our findings provide evidence on the pathogenesis of ALS, potential targets for the development of new drugs for ALS, and important markers for predicting ALS prognosis.

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“…STAT5 activation occurs primarily through the activation of JAK1 and JAK3. Yet the SOCS, PTPs, and PIAS are the main negative regulators of JAK-STAT signal [ 23 ]. Overexpression of SOCS1 leads to a decrease in p-JAKs and p-STATs; PIAS1 and PIAS3 can inhibit the binding of STATs to target gene promoters by coupling with STATs molecules and inhibit the transcriptional activity of STATs by modifying the phosphorylation sites of STATs [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Sishen-Pill-Regulated Special Memory T and mTfh Cell via Involving JAK/STAT5 Pathway in Colitis Mice

Wang

Huang

Kang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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It is known that memory T cells (mT cell) and memory T follicular cells (mTfh) play vital roles in the IBD pathogenesis. Sishen Pill (SSP) is a classic prescription used to treat chronic ulcerative colitis (UC). However, it is still unclear whether SSP can regulate immune homeostasis induced by mT cell and mTfh to treat IBD. In this study, we measured mT cell and mTfh level to explore the conceivable mechanism of SSP-treated IBD. The mice colitis were induced by dextran sulfate sodium (DSS) and were treated by SSP for 7 days. The therapeutic effect of SSP was evaluated by macroscopic and microscopic observation; the mT cell, mTfh, and their subsets were analyzed by flow cytometry. Activation of the JAK/STAT signaling pathway was analyzed by using a Western blot. In the present study, SSP significantly reversed weight loss and colonic injury (colon weight increase and colonic length shortening) caused by 3% DSS in physiological saline solution. Flow cytometry showed that the percentages of CD4+ and CD8+ expressions on central memory T cells were enhanced after SSP treatment, while the CD4+ T cm, CD4+ mTfh (memory T follicular helper) cells and their subpopulations were also significantly increased. Moreover, SSP inhibited the expression of JAK/STAT signaling pathway proteins JAK1, PIAS3, STAT5, p-STAT5, BIM, BAX, caspase-3, and β-casein and promoted the expression of JAK3, PISA1, Bcl-2, and caveolin-1. In summary, SSP can regulate immune homeostasis induced by mT cell and mTfh in DSS-induced colitis, which is potentially correlated with JAK/STAT signaling pathway activation.

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A centric view of JAK/STAT5 in intestinal homeostasis, infection, and inflammation

Cited by 18 publications

References 103 publications

Identification of an evolutionarily conserved domain in Neurod1 favouring enteroendocrine versus goblet cell fate

Identification of an evolutionarily conserved domain in Neurod1 favouring enteroendocrine versus goblet cell fate

Identification of Regulatory Factors and Prognostic Markers in Amyotrophic Lateral Sclerosis

Mechanism of Sishen-Pill-Regulated Special Memory T and mTfh Cell via Involving JAK/STAT5 Pathway in Colitis Mice

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