Small-molecule modulators of INAVA cytosolic condensate and cell–cell junction assemblies

Chang, Denis; Luong, Phi; Li, Qian; LeBarron, Jamie; Anderson, Michael D.; Barrett, Lee; Lencer, Wayne I.

doi:10.1083/jcb.202007177

Cited by 4 publications

(3 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, despite increased claudin-2 expression in human disease 64 , 86 , 87 , 92 , 175 , 176 and experimental data showing that claudin-2-dependent pore pathway permeability increases exacerbate disease in mice 50 , 98 , 100 , the relevance of claudin-2 to human intestinal disease remains to be determined. Our understanding of how barrier function and disease are affected by polymorphisms in barrier-related genes associated with IBD, including INAVA 177 – 179 and CDH1 (refs. 180 , 181 ), which encode innate immune activator and E-cadherin, respectively, is even more limited.…”

Section: Discussionmentioning

confidence: 99%

Paracellular permeability and tight junction regulation in gut health and disease

Horowitz

Chánez-Paredes

Haest

et al. 2023

Nat Rev Gastroenterol Hepatol

137

View full text Add to dashboard Cite

Epithelial tight junctions define the paracellular permeability of the intestinal barrier. Molecules can cross the tight junctions via two distinct size-selective and charge-selective paracellular pathways: the pore pathway and the leak pathway. These can be distinguished by their selectivities and differential regulation by immune cells. However, permeability increases measured in most studies are secondary to epithelial damage, which allows non-selective flux via the unrestricted pathway. Restoration of increased unrestricted pathway permeability requires mucosal healing. By contrast, tight junction barrier loss can be reversed by targeted interventions. Specific approaches are needed to restore pore pathway or leak pathway permeability increases. Recent studies have used preclinical disease models to demonstrate the potential of pore pathway or leak pathway barrier restoration in disease. In this Review, we focus on the two paracellular flux pathways that are dependent on the tight junction. We discuss the latest evidence that highlights tight junction components, structures and regulatory mechanisms, their impact on gut health and disease, and opportunities for therapeutic intervention.

show abstract

Section: Discussionmentioning

confidence: 99%

Paracellular permeability and tight junction regulation in gut health and disease

Horowitz

Chánez-Paredes

Haest

et al. 2023

Nat Rev Gastroenterol Hepatol

137

View full text Add to dashboard Cite

show abstract

“…INAVA, known as Innate Immunity Activator, is a risk gene for inflammatory bowel disease specifically expressed by mucosal surface epithelial cells. Recent studies have shown that it is associated with tumorigenesis and inflammatory responses ( Chang et al, 2021 ). INAVA expression is associated with regulating two transcription factors, ELF5 and GATA3, which are important in breast stem cells, and targeting INAVA has therapeutic value in breast cancer ( Ma et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of the Diagnostic Characteristic Genes of Ovarian Cancer by Bioinformatics and Machine Learning

Liu

Antwi

et al. 2022

Front. Genet.

View full text Add to dashboard Cite

Background: Ovarian cancer (OC) has a high mortality rate and poses a severe threat to women’s health. However, abnormal gene expression underlying the tumorigenesis of OC has not been fully understood. This study aims to identify diagnostic characteristic genes involved in OC by bioinformatics and machine learning.Methods: We utilized five datasets retrieved from the Gene Expression Omnibus (GEO) database, The Cancer Genome Atlas (TCGA) database, and the Genotype-Tissue Expression (GTEx) Project database. GSE12470 and GSE18520 were combined as the training set, and GSE27651 was used as the validation set A. Also, we combined the TCGA database and GTEx database as validation set B. First, in the training set, differentially expressed genes (DEGs) between OC and non-ovarian cancer tissues (nOC) were identified. Next, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Disease Ontology (DO) enrichment analysis, and Gene Set Enrichment Analysis (GSEA) were performed for functional enrichment analysis of these DEGs. Then, two machine learning algorithms, Least Absolute Shrinkage and Selector Operation (LASSO) and Support Vector Machine-Recursive Feature Elimination (SVM-RFE), were used to get the diagnostic genes. Subsequently, the obtained diagnostic-related DEGs were validated in the validation sets. Then, we used the computational approach (CIBERSORT) to analyze the association between immune cell infiltration and DEGs. Finally, we analyzed the prognostic role of several genes on the KM-plotter website and used the human protein atlas (HPA) online database to analyze the expression of these genes at the protein level.Results: 590 DEGs were identified, including 276 upregulated and 314 downregulated DEGs.The Enrichment analysis results indicated the DEGs were mainly involved in the nuclear division, cell cycle, and IL−17 signaling pathway. Besides, DEGs were also closely related to immune cell infiltration. Finally, we found that BUB1, FOLR1, and PSAT1 have prognostic roles and the protein-level expression of these six genes SFPR1, PSAT1, PDE8B, INAVA and TMEM139 in OC tissue and nOC tissue was consistent with our analysis.Conclusions: We screened nine diagnostic characteristic genes of OC, including SFRP1, PSAT1, BUB1B, FOLR1, ABCB1, PDE8B, INAVA, BUB1, TMEM139. Combining these genes may be useful for OC diagnosis and evaluating immune cell infiltration.

show abstract

“…Induced cytosolic condensates promote ubiquitination of sequestered effectors to promote inflammatory signaling ( Luong et al, 2018 ). Like inhibitors of BCL6, the inhibitors of the Rho-ROCK pathway promoted the recruitment of an E3 ubiquitin ligase to INAVA cytosolic condensates and mediated ubiquitination and proteasomal degradation ( Chang et al, 2021 ).…”

Section: Classification Of C-modsmentioning

confidence: 99%

Principles and functions of condensate modifying drugs

Patel¹,

Mitrea²,

Namasivayam

et al. 2022

Front. Mol. Biosci.

View full text Add to dashboard Cite

Biomolecular condensates are compartmentalized communities of biomolecules, which unlike traditional organelles, are not enclosed by membranes. Condensates play roles in diverse cellular processes, are dysfunctional in many disease states, and are often enriched in classically “undruggable” targets. In this review, we provide an overview for how drugs can modulate condensate structure and function by phenotypically classifying them as dissolvers (dissolve condensates), inducers (induce condensates), localizers (alter localization of the specific condensate community members) or morphers (alter the physiochemical properties). We discuss the growing list of bioactive molecules that function as condensate modifiers (c-mods), including small molecules, oligonucleotides, and peptides. We propose that understanding mechanisms of condensate perturbation of known c-mods will accelerate the discovery of a new class of therapies for difficult-to-treat diseases.

show abstract

Small-molecule modulators of INAVA cytosolic condensate and cell–cell junction assemblies

Cited by 4 publications

References 55 publications

Paracellular permeability and tight junction regulation in gut health and disease

Paracellular permeability and tight junction regulation in gut health and disease

Identification and Validation of the Diagnostic Characteristic Genes of Ovarian Cancer by Bioinformatics and Machine Learning

Principles and functions of condensate modifying drugs

Contact Info

Product

Resources

About