An inflammatory bowel disease–risk variant in INAVA decreases pattern recognition receptor–induced outcomes

Yan, Jie; Hedl, Matija; Abraham, Clara

doi:10.1172/jci86282

Cited by 25 publications

(26 citation statements)

References 60 publications

(63 reference statements)

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“…We asked if similar genotype-dependent regulation was observed in response to IL-1β treatment. As predicted from our previous results ( Yan et al, 2017 ), IL-1β-treated MDMs from rs7554511 CC IBD risk carriers showed reduced INAVA protein expression compared to MDMs derived from AA carriers ( Figure 4A ). Also consistent with our in vitro results, both IL-1β-induced NF-κB and MAPK signaling ( Figure 4B ), and cytokine secretion ( Figure 4C ), were reduced in MDMs from rs7554511 CC IBD risk carriers.…”

Section: Resultssupporting

confidence: 89%

“…To further address the relevance of these findings, we prepared primary monocyte-derived human macrophages (MDMs) from individuals carrying the INAVA-IBD rs7554511 CC risk allele. These cells have reduced INAVA expression and impaired signaling and cytokine secretion in response to PRR stimulation ( Yan et al, 2017 ). We asked if similar genotype-dependent regulation was observed in response to IL-1β treatment.…”

Section: Resultsmentioning

confidence: 99%

“…And it does not form cytosolic puncta, which we suggest represent protein complexes required for signal transduction (signalosomes). In macrophages, the C-terminal region of INAVA is also implicated in inflammatory signaling by mediating scaffolding for NOD2 interacting proteins ( Yan et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…Mice lacking the protein altogether show defects in intestinal barrier integrity at steady state and greater susceptibility to mucosal infection ( Mohanan et al, 2018 ). Human macrophages carrying the IBD rs7554511 risk allele have decreased INAVA expression and show multiple defects in myeloid function, including in innate immune NOD2 signaling and cytokine secretion, and in microbial clearance in association with reduced autophagy and ROS production ( Yan et al, 2017 ). Each process is well known to affect gut function in health and disease, but the molecular mechanisms for how they are regulated or interconnected by INAVA are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

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INAVA-ARNO complexes bridge mucosal barrier function with inflammatory signaling

Luong

Hedl

Yan

et al. 2018

eLife

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Homeostasis at mucosal surfaces requires cross-talk between the environment and barrier epithelial cells. Disruption of barrier function typifies mucosal disease. Here we elucidate a bifunctional role in coordinating this cross-talk for the inflammatory bowel disease risk-gene INAVA. Both activities require INAVA’s DUF3338 domain (renamed CUPID). CUPID stably binds the cytohesin ARF-GEF ARNO to effect lateral membrane F-actin assembly underlying cell-cell junctions and barrier function. Unexpectedly, when bound to CUPID, ARNO affects F-actin dynamics in the absence of its canonical activity as a guanine nucleotide-exchange factor. Upon exposure to IL-1β, INAVA relocates to form cytosolic puncta, where CUPID amplifies TRAF6-dependent polyubiquitination and inflammatory signaling. In this case, ARNO binding to CUPID negatively-regulates polyubiquitination and the inflammatory response. INAVA and ARNO act similarly in primary human macrophages responding to IL-1β and to NOD2 agonists. Thus, INAVA-CUPID exhibits dual functions, coordinated directly by ARNO, that bridge epithelial barrier function with extracellular signals and inflammation.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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INAVA-ARNO complexes bridge mucosal barrier function with inflammatory signaling

Luong

Hedl

Yan

et al. 2018

eLife

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“…Thus, targeted screening for WFDC2 protein inhibition might bene ts for the treatment of ovarian cancer. INAVA gene, also called C1orf106, has been recently reported essential for optimal MAPK and NF-κB activation in primary human cells by recruiting 14-3-3τ [39]. And in ammatory bowel disease (IBD) associated polymorphisms in INAVA is revealed to play important roles in intestinal immune homeostasis by regulating pattern recognition receptor (PRR) mediated signaling transduction and bacterial clearance.…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis based gene expressional profiling reveals functional genes in ovarian cancer

Zhao

Zhang

et al. 2020

Preprint

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Background Ovarian cancer causes high mortality rate worldwide, and despite numerous attempts, the outcome for patients with ovarian cancer are still not well improved. Microarray based gene expressional analysis provides with valuable information for discriminating functional genes in ovarian cancer development and progression. However, due to the differences in experimental design, the results varied significantly across individual datasets. Methods In the present study, the data of gene expression in ovarian cancer was downloaded from Gene Expression Omnibus and 16 studies were included. A meta-analysis based gene expression analysis was performed to identify differentially expressed genes (DEGs). The most differentially expressed genes in our meta-analysis were selected for gene expression and gene function validation. Results A total of 972 DEGs with P -value<0.001 were identified in ovarian cancer, including 541 up-regulated genes and 431 down-regulated genes, among which 92 additional DEGs were found as gained DEGs. Top five up-and down-regulated genes were selected for the validation of gene expressional profiling. Among these genes, up-regulated CD24 , SOX17 , WFDC2 , EPCAM , INAVA , and down-regulated AOX1 were revealed to be with consistent expressional patterns in clinical patient samples of ovarian cancer. Gene functional analysis demonstrated that up-regulated WFCD2 and INAVA promoted ovarian cancer cell migration, WFDC2 enhanced cell proliferation, while down-regulated AOX1 was functional in inducing cell apoptosis of ovarian cancer. Interestingly. Conclusion Our study shed light on the molecular mechanisms underlying the development of ovarian cancer, and facilitated the understanding of novel diagnostic and therapeutic targets in ovarian cancer.

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Takayasu arteritis in an adolescent with Crohn’s disease

et al. 2021

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Crohn’s disease (CD) and Takayasu arteritis (TA) are two distinct clinical entities. Τhe likelihood of both diseases coexisting is low, and although CD co-occurs with all types of vasculitis, TA is the most common subtype. Herein, the case of a 15-year-old female, diagnosed with TA following an initial diagnosis of CD, is reported. A review of the literature, including a systemic review of the case reports and case series of children and adolescents up to the age of 21, with both CD and TA, follows the case description. In total, 28 cases of TA and CD were retrieved. The median age of patients was 14.8 years, they were mostly females (72%) and the median time between the two diagnoses was 3.7 years. In the majority of cases, CD was diagnosed first and TA followed. Computed tomography angiography and magnetic resonance angiography were the preferred imaging modalities to assist diagnosis.

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An inflammatory bowel disease–risk variant in INAVA decreases pattern recognition receptor–induced outcomes

Cited by 25 publications

References 60 publications

INAVA-ARNO complexes bridge mucosal barrier function with inflammatory signaling

INAVA-ARNO complexes bridge mucosal barrier function with inflammatory signaling

Meta-analysis based gene expressional profiling reveals functional genes in ovarian cancer

Takayasu arteritis in an adolescent with Crohn’s disease

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