Small noncoding vault RNA2‐1 disrupts gut epithelial barrier function via interaction with HuR

Abstract

Vault RNAs (vtRNAs) are small noncoding RNAs and highly expressed in many eukaryotes. Here, we identified vtRNA2‐1 as a novel regulator of the intestinal barrier via interaction with RNA‐binding protein HuR. Intestinal mucosal tissues from patients with inflammatory bowel diseases and from mice with colitis or sepsis express increased levels of vtRNAs relative to controls. Ectopically expressed vtRNA2‐1 decreases the levels of intercellular junction (IJ) proteins claudin 1, occludin, and E‐cadherin and causes intestinal epithelial barrier dysfunction in vitro, whereas vtRNA2‐1 silencing promotes barrier function. Increased vtRNA2‐1 also decreases IJs in intestinal organoid, inhibits epithelial renewal, and causes Paneth cell defects ex vivo. Elevating the levels of tissue vtRNA2‐1 in the intestinal mucosa increases the vulnerability of the gut barrier to septic stress in mice. vtRNA2‐1 interacts with HuR and prevents HuR binding to claudin 1 and occludin mRNAs, thus decreasing their translation. These results indicate that vtRNA2‐1 impairs intestinal barrier function by repressing HuR‐facilitated translation of claudin 1 and occludin.

Control of Paneth cell function by HuR regulates gut mucosal growth by altering stem cell activity

“…Our study further shows that increasing the levels of cellular HuR blocked miR-195 association with the Phb1 mRNA and that miR-195 overexpression abolished HuR-induced stimulation of PHB1 expression. As reported previously ( Xiao & Wang, 2014 ; Wang et al, 2017 ; Ma et al, 2023 ), HuR can perform its regulatory function by antagonizing miRNAs and small ncRNAs besides its RNA binding affinity. For example, HuR antagonizes miR-548c-3p to regulate the expression of TOP2A ( Srikantan et al, 2011 ), prevents miR-122-mediated repression of CAT-1 expression ( Bhattacharyya et al, 2006 ), blocks miR-494 to regulate the expression of nucleolin ( Tominaga et al, 2011 ), and co-operates with let-7 in repressing c-Myc expression ( Kim et al, 2009 ).…”

Human Vault RNAs: Exploring Their Potential Role in Cellular Metabolism

“…The symbiosis between host and microbes is crucial for avoiding many immune-related disorders, such as inflammatory bowel disease (IBS), cardiometabolic disease, and cancer (reviewed in [117]). A recently published paper also showed the role of vtRNA2-1 in disrupting the gut epithelial barrier via interaction with HuR, one of the RNA-binding proteins [102]. Increased levels of this vault RNA were observed in intestinal mucosal tissue samples from patients with IBS and samples from mice with colitis or sepsis.…”

“…The results observed in mice agreed with those from in vitro experiments. Mechanistically, vtRNA2-1 interaction with HuR prevents HuR binding to claudin 1 and occludin mRNA and decreases their translation [102].…”

Crosstalk between vault RNAs and innate immunity

“…Ectopic expression of vtRNA 2-1 decreases the interaction between HuR and the mRNAs of intercellular junction proteins, thereby suppressing cell proliferation in primary cultures of intestinal organoids and inhibiting intestinal mucosal growth in mouse models. These effects contribute to epithelial barrier dysfunction and sepsis-related stress [ 103 ]. The HuR protein has been strongly suggested to be a mediator of the inflammatory response.…”

“…vtRNAs are involved in diverse cellular processes, including innate immunity [ 84 , 97 , 98 , 103 ], cell differentiation [ 115 ], cell survival [ 116 ], and cellular homeostasis [ 87 , 117 ]. The expression of vtRNAs has been associated with specific tissues and cells depending on their physiological state.…”