An essential role for the antiviral endoribonuclease, RNase-L, in antibacterial immunity

Li, Xiaoling; Ezelle, Heather J.; Kang, Tae-Jin; Zhang, Lei; Shirey, Kari Ann; Harro, Janette M.; Hasday, Jeffrey D.; Mohapatra, Saroj Kant; Crasta, Oswald; Vogel, Stefanie N.; Cross, Alan S.; Hassel, Bret A.

doi:10.1073/pnas.0807265105

Cited by 58 publications

(56 citation statements)

References 35 publications

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“…These findings indicate that RNase L functions to increase IFN-␤ induction and to reduce TNF-␣; thus, the inhibition of RNase L by WT EPEC is an important mechanism by which it modulates host cytokine expression. Furthermore, while viruses have evolved multiple strategies to evade the antiviral activities of RNase L (67,82), to our knowledge, this is the first example of RNase L inhibition mediated by a bacterial pathogen and supports an important role for RNase L in antibacterial immunity (45,51,52).…”

Section: Discussionsupporting

confidence: 52%

“…Therefore, RNase L may contribute to IFN-mediated GI functions by multiple mechanisms. In support of this view, we previously identified a role for RNase L in antibacterial immunity (52) and recently reported a protective role for RNase L in the immune response to commensal bacteria following GI injury in a mouse colitis model (45). This protective effect corresponded to an RNase L-dependent increase in IFN induction, suggesting that RNase L is an important mediator of IFN functions in the GI tract.…”

mentioning

confidence: 59%

“…5C). Reports from our laboratory and others have demonstrated that RNase L regulates the induction of IFN-␤ and TNF-␣ in response to microbial stimuli (45,47,52,69,81) and suggested a potential mechanism in which the T3SS-dependent regulation of these cytokines is mediated, in part, through RNase L. In support of this model, inhibition of RNase L activity by WT EPEC corresponded to diminished IFN-␤ induction and increased TNF-␣, whereas infection with T3SS-deficient EPEC resulted in an RNase L-dependent increase in IFN-␤ induction and decrease in TNF-␣ (Fig. 5A and B).…”

Section: Discussionmentioning

confidence: 99%

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Enteropathogenic Escherichia coli Inhibits Type I Interferon- and RNase L-Mediated Host Defense To Disrupt Intestinal Epithelial Cell Barrier Function

et al. 2014

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EnteropathogenicEscherichia coli(EPEC) primarily infects children in developing countries and causes diarrhea that can be deadly. EPEC pathogenesis occurs through type III secretion system (T3SS)-mediated injection of effectors into intestinal epithelial cells (IECs); these effectors alter actin dynamics, modulate the immune response, and disrupt tight junction (TJ) integrity. The resulting compromised barrier function and increased gastrointestinal (GI) permeability may be responsible for the clinical symptoms of infection. Type I interferon (IFN) mediates anti-inflammatory activities and serves essential functions in intestinal immunity and homeostasis; however, its role in the immune response to enteric pathogens, such as EPEC, and its impact on IEC barrier function have not been examined. Here, we report that IFN-β is induced following EPEC infection and regulates IEC TJ proteins to maintain barrier function. The EPEC T3SS effector NleD counteracts this protective activity by inhibiting IFN-β induction and enhancing tumor necrosis factor alpha to promote barrier disruption. The endoribonuclease RNase L is a key mediator of IFN induction and action that promotes TJ protein expression and IEC barrier integrity. EPEC infection inhibits RNase L in a T3SS-dependent manner, providing a mechanism by which EPEC evades IFN-induced antibacterial activities. This work identifies novel roles for IFN-β and RNase L in IEC barrier functions that are targeted by EPEC effectors to escape host defense mechanisms and promote virulence. The IFN-RNase L axis thus represents a potential therapeutic target for enteric infections and GI diseases involving compromised barrier function.

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Section: Discussionsupporting

confidence: 52%

mentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

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Enteropathogenic Escherichia coli Inhibits Type I Interferon- and RNase L-Mediated Host Defense To Disrupt Intestinal Epithelial Cell Barrier Function

et al. 2014

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“…Our findings show a novel biological activity of RNase L as an inducer of autophagy. The implications are that RNase L not only causes degradation of single-stranded RNA but also contributes to the disposal of organelles, long-lived proteins, and microbes, perhaps including bacteria (23), during the host response to invading pathogens.…”

Section: Discussionmentioning

confidence: 99%

RNase L Triggers Autophagy in Response to Viral Infections

Chakrabarti

Ghosh

Banerjee

et al. 2012

J Virol

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Autophagy is a programmed homeostatic response to diverse types of cellular stress that disposes of long-lived proteins, organelles, and invading microbes within double-membraned structures called autophagosomes. The 2=,5=-oligoadenylate/ RNase L system is a virus-activated host RNase pathway that disposes of or processes viral and cellular single-stranded RNAs. Here we report that activation of RNase L during viral infections induces autophagy. Accordingly, infections with encephalomyocarditis virus or vesicular stomatitis virus led to higher levels of autophagy in wild-type mouse embryonic fibroblasts (MEF) than in RNase L-null MEF. Similarly, direct activation of RNase L with a 2=,5=-oligoadenylate resulted in p62(SQSTM1) degradation, LC3BI/LC3BII conversion, and appearance of autophagosomes. To determine the effect of RNase L-mediated autophagy on viral replication, we compared viral yields in wild A utophagy (or "self-eating") is an essential and ancient cellular process for degrading and recycling components of longlived proteins, organelles, and microbial invaders (7,22). These materials are sequestered in the cytoplasm within double-membrane vesicles termed autophagosomes that fuse with lysosomes, causing the contents to be degraded. While autophagy is often induced in response to viral infections, the impact of autophagy on pathogenesis and virus replication can be unpredictable. For instance, intracerebral injection of Sindbis virus in mice induced autophagy, causing degradation of viral proteins while promoting viral clearance and protecting against virus-mediated neuronal cell death (32). However, while animal survival was enhanced by autophagy there was no effect on virus replication. There is also a complex, reciprocal relationship between autophagy and the mammalian immune system (22). The fact that many viruses have evolved strategies for countering and/or subverting autophagy supports a role for autophagy in the host antiviral response (31, 43). As an example of cross talk between autophagy and the innate immune response, autophagy mediates cellular recognition of some single-strand RNA (ssRNA) viruses, leading to alpha interferon (IFN-␣) induction in plasmacytoid dendritic cells (20). In addition, downstream events in IFN-regulated pathways regulate the autophagocytic process itself. For instance, PKR is an IFNinducible serine/threonine protein kinase that inhibits translation by phosphorylating eIF2␣ and that promotes autophagocytic degradation of HSV-1 (37, 38). Effects of PKR on both translation and autophagy are blocked by the HSV-1 neurovirulence gene product ICP34.5, which redirects protein phosphatase 1␣ to dephosphorylate eIF2␣. Here we implicate a second IFN-regulated pathway, the 2=,5=-oligoadenylate (OAS)/RNase L system (3, 34), in the control of autophagy.OASs are IFN-inducible pathogen recognition receptors (PRR) that produce 2=,5=-linked oligonucleotides of the formula p x 5=A(2=p5=A) n (x ϭ 1 to 3; n Ն 2) (2-5A) from ATP in response to viral double-stranded RNA (dsRNA) (15). The ...

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“…and Escherichia coli (E. coli) have been reported [250]. RNase L deficient mice, when compared to wild type mice, demonstrated much lower levels of pro--inflammatory cytokine production, which could explain why these RNase L deficient mice have a higher bacterial titer and mortality when faced with B. anthrasis and E. coli infection [250].…”

Section: The Antibacterial Effects Of Rnase L Against Bacillus Anthramentioning

confidence: 99%

Characterization of the termini of the West Nile virus genome and their interactions with the small isoform of the 2′ 5′-oligoadenylate synthetase family

Deo

Patel

Chojnowski

et al. 2015

Journal of Structural Biology

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confirmed the specificity of the interaction. Solution conformations of both the 5'--TR RNA of WNV and OAS1 were then elucidated using small--angle x--ray scattering. I also report that the 3' terminal region (3'--TR) is able to mediate specific interaction with and activation of OAS1. Binding and kinetic experiments identified a specific stem loop within the 3'--TR that is sufficient for activation of the enzyme. The solution confirmation of the 3'--terminal region was determined by small angle X--ray scattering, and computational models suggest a conformationally restrained structure comprised of a helix and short stem loop. Structural investigation of the 3'--ii TR in complex with OAS1 is also presented. Finally, we show that genome cyclization by base pairing between the 5'--and 3'--TRs, a required step for replication, is not sufficient to protect WNV from OAS1 recognition. The purity, monodispersity and homogeneity of all samples subjected to SAXS analysis were evaluated using dynamic light scattering and/or analytical ultra--centrifuge. These data provide a framework for understanding recognition of the highly structured terminal regions of a flaviviral genome by an innate immune enzyme.iii

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An essential role for the antiviral endoribonuclease, RNase-L, in antibacterial immunity

Cited by 58 publications

References 35 publications

Enteropathogenic Escherichia coli Inhibits Type I Interferon- and RNase L-Mediated Host Defense To Disrupt Intestinal Epithelial Cell Barrier Function

Enteropathogenic Escherichia coli Inhibits Type I Interferon- and RNase L-Mediated Host Defense To Disrupt Intestinal Epithelial Cell Barrier Function

RNase L Triggers Autophagy in Response to Viral Infections

Characterization of the termini of the West Nile virus genome and their interactions with the small isoform of the 2′ 5′-oligoadenylate synthetase family

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