Diminished nuclear RNA decay upon Salmonella infection upregulates antibacterial noncoding RNA s

Abstract

Cytoplasmic mRNA degradation controls gene expression to help eliminate pathogens during infection. However, it has remained unclear whether such regulation also extends to nuclear RNA decay. Here, we show that 145 unstable nuclear RNAs, including enhancer RNAs (eRNAs) and long noncoding RNAs (lncRNAs) such as NEAT1v2, are stabilized upon infection in HeLa cells. In uninfected cells, the RNA exosome, aided by the Nuclear EXosome Targeting (NEXT) complex, degrades these labile transcripts. Upon infection, the levels of the exosome/NEXT components, RRP6 and MTR4, dramatically decrease, resulting in transcript stabilization. Depletion of lncRNAs, NEAT1v2, or eRNA07573 in HeLa cells triggers increased susceptibility to infection concomitant with the deregulated expression of a distinct class of immunity-related genes, indicating that the accumulation of unstable nuclear RNAs contributes to antibacterial defense. Our results highlight a fundamental role for regulated degradation of nuclear RNA in the response to pathogenic infection.

Not lost in host translation: The new roles of long noncoding RNAs in infectious diseases

“…Thus, the notion that lncRNAs can act as competitors with mRNAs in vivo remains debated (Denzler, Agarwal, Stefano, Bartel, & Stoffel, ). Interestingly, mechanisms regulating lncRNA decay during infection exist, as recently shown upon Salmonella infection (Imamura et al, ). Moreover, prediction of lncRNA function by considering lncRNA–miRNA–mRNA crosstalk have been very informative for identifying the participation of the lncRNA MEG3 in pathways related to autophagy in macrophages infected with Mycoplasma bovis Bacillus Calmette–Guérin (BCG; Pawar, Hanisch, Palma Vera, Einspanier, & Sharbati, ).…”

“…In the nucleus, lncRNAs regulate gene expression in trans through the recruitment of proteins or molecular complexes at specific loci or in cis , through their unique cis ‐regulatory capacity at neighbouring loci. Examples of cis ‐regulatory lncRNAs are enhancer RNAs (eRNAs), recently shown to be upregulated in response to Salmonella infection (Imamura et al, ). Interestingly, lncRNAs have also been detected in the cytoplasm arguing for potential cytoplasmic functions (Kretz et al, ; Rashid, Shah, & Shan, ; and for review: Carlevaro‐Fita & Johnson, ).…”

Nuclear lnc RNA stabilization in the host response to bacterial infection

“…Host cells utilize micro RNA s (e.g., let‐7, miR‐15, miR‐30, miR‐128, miR‐146, miR‐155) and lnc RNA s (e.g., Ne ST ) to respond to Salmonella infection. Imamura et al () now report loss of nuclear RNA degradation factors and accumulation of unstable nuclear lnc RNA s in response to intracellular Salmonella growth. These lnc RNA candidates may contribute to host defense mechanisms that help clear the invading pathogen.…”

“…Beyond individual examples, RNA‐seq profiling of various cell types infected with Salmonella has provided a treasure trove of lncRNAs that are regulated upon immune cell stimulation or pathogen invasion (Westermann et al , ; Avraham et al , ; Haber et al , ; Saliba et al , ), but their molecular functions remain uncharacterized. In this issue of The EMBO Journal , Imamura et al (), report the exciting observation that nuclear RNA degradation is dysregulated as Salmonella replicates inside host cells, prompting the accumulation of a distinct group of otherwise unstable lncRNAs, some of which are suggested to be important for antibacterial defense.…”

“…The authors also obtained results to suggest that these nuclear lncRNAs are stabilized because they are required for effective host defense (Imamura et al , ). They show that NEAT1 knockout cells (lacking both the NEAT1_1 (3.7 kb) and NEAT1_2 (23 kb) isoforms) are more permissive to Salmonella infection and that there is a set of 126 genes, including those of several immune regulators, whose induction upon infection requires an intact NEAT1 locus.…”