The RIG-I-like Receptor LGP2 Controls CD8+ T Cell Survival and Fitness

Suthar, Mehul S.; Ramos, Hilario J.; Brassil, Margaret M.; Netland, Jason; Chappell, Craig P.; Blahnik, Gabriele; McMillan, Aimee; Diamond, Michael S.; Clark, Edward A.; Bevan, Michael J.; Gale, Michael

doi:10.1016/j.immuni.2012.07.004

Cited by 110 publications

(114 citation statements)

References 46 publications

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“…The central role of MAVS-dependent signaling in controlling WNV infection and pathogenesis has been established and implicates an essential role for RLRs in immunity against WNV (12,14,29,47). Herein, we delineated the role of RIG-I and MDA5 as individual PRRs in contributing to the control of WNV and induction of innate immune genes in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…MDA5 Ϫ/Ϫ mice were kindly provided by M. Colonna (Washington University, St. Louis, MO). MAVS Ϫ/Ϫ mice were previously described (47). For production of double knockout (DKO) mice lacking both RIG-I and MDA5, RIG-I Ϫ/Ϫ and MDA5 Ϫ/Ϫ mice were intercrossed, and the resulting DKO offspring were backcrossed into a C57BL/6 background through the F3 generation.…”

Section: Mouse Studies Rig-imentioning

confidence: 99%

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The Essential, Nonredundant Roles of RIG-I and MDA5 in Detecting and Controlling West Nile Virus Infection

Errett

Suthar

McMillan

et al. 2013

J Virol

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182

158

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Virus recognition and response by the innate immune system are critical components of host defense against infection. Activation of cell-intrinsic immunity and optimal priming of adaptive immunity against West Nile virus (WNV), an emerging vectorborne virus, depend on recognition by RIG-I and MDA5, two cytosolic pattern recognition receptors (PRRs) of the RIG-I-like receptor (RLR) protein family that recognize viral RNA and activate defense programs that suppress infection. We evaluated the individual functions of RIG-I and MDA5 both in vitro and in vivo in pathogen recognition and control of WNV. Lack of RIG-I or MDA5 alone results in decreased innate immune signaling and virus control in primary cells in vitro and increased mortality in mice. We also generated RIG-I ؊/؊ ؋ MDA5 ؊/؊ double-knockout mice and found that a lack of both RLRs results in a complete absence of innate immune gene induction in target cells of WNV infection and a severe pathogenesis during infection in vivo, similar to findings for animals lacking MAVS, the central adaptor molecule for RLR signaling. We also found that RNA products from WNV-infected cells but not incoming virion RNA display at least two distinct pathogen-associated molecular patterns (PAMPs) containing 5= triphosphate and double-stranded RNA that are temporally distributed and sensed by RIG-I and MDA5 during infection. Thus, RIG-I and MDA5 are essential PRRs that recognize distinct PAMPs that accumulate during WNV replication. Collectively, these experiments highlight the necessity and function of multiple related, cytoplasmic host sensors in orchestrating an effective immune response against an acute viral infection.

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Section: Discussionmentioning

confidence: 99%

Section: Mouse Studies Rig-imentioning

confidence: 99%

The Essential, Nonredundant Roles of RIG-I and MDA5 in Detecting and Controlling West Nile Virus Infection

Errett

Suthar

McMillan

et al. 2013

J Virol

Self Cite

182

158

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“…F9 embryonal carcinoma cells were obtained from ATCC and cultured as above on tissue culture plates coated with 0.1% gelatin. Dhx58 −/− mice were kindly provided by Dr. Michael Gale Jr (Suthar et al , 2012) and maintained and bred in accordance with national and institutional guidelines for animal care. Dhx58 +/+ , Dhx58 +/− and Dhx58 −/− MEFs were generated from day 13.5 embryos from Dhx58 +/− intercrosses and immortalised using a minimal dose of a retroviral vector encoding large T antigen as previously described (Schulz et al , 2010).…”

Section: Methodsmentioning

confidence: 99%

“…Loss of LGP2 therefore leads to increased sensitivity to viruses detected by MDA5 such as picornaviridae (Venkataraman et al , 2007; Satoh et al , 2010). LGP2 may also impact RIG‐I signalling (Rothenfusser et al , 2005; Yoneyama et al , 2005), and alternative functions have been suggested by the fact that LGP2‐deficient mice have impaired CD8 + T‐cell responses to West Nile virus or lymphocytic choriomeningitis virus that appear unrelated to IFN production (Suthar et al , 2012). …”

Section: Introductionmentioning

confidence: 99%

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

et al. 2018

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In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG‐I‐like receptor (RLR) family, which signal to induce production of type I interferons (IFN). These key antiviral cytokines act in a paracrine and autocrine manner to induce hundreds of interferon‐stimulated genes (ISGs), whose protein products restrict viral entry, replication and budding. ISGs include the RLRs themselves: RIG‐I, MDA5 and, the least‐studied family member, LGP2. In contrast, the IFN system is absent in plants and invertebrates, which defend themselves from viral intruders using RNA interference (RNAi). In RNAi, the endoribonuclease Dicer cleaves virus‐derived double‐stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that target complementary viral RNA for cleavage. Interestingly, the RNAi machinery is conserved in mammals, and we have recently demonstrated that it is able to participate in mammalian antiviral defence in conditions in which the IFN system is suppressed. In contrast, when the IFN system is active, one or more ISGs act to mask or suppress antiviral RNAi. Here, we demonstrate that LGP2 constitutes one of the ISGs that can inhibit antiviral RNAi in mammals. We show that LGP2 associates with Dicer and inhibits cleavage of dsRNA into siRNAs both in vitro and in cells. Further, we show that in differentiated cells lacking components of the IFN response, ectopic expression of LGP2 interferes with RNAi‐dependent suppression of gene expression. Conversely, genetic loss of LGP2 uncovers dsRNA‐mediated RNAi albeit less strongly than complete loss of the IFN system. Thus, the inefficiency of RNAi as a mechanism of antiviral defence in mammalian somatic cells can be in part attributed to Dicer inhibition by LGP2 induced by type I IFNs. LGP2‐mediated antagonism of dsRNA‐mediated RNAi may help ensure that viral dsRNA substrates are preserved in order to serve as targets of antiviral ISG proteins.

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“…This pathway is a subtype of pattern recognition receptors responsible for primary recognition of pathogen and host-associated molecular patterns and the subsequent activation of type I IFN production that orchestrates an innate immune response (22)(23)(24). In addition to its role in inhibiting IFNβ expression, Suthar et al recently demonstrated that LGP2 governs CD8+ T-cell fitness and survival by inhibiting death-receptor signaling (25). Here we demonstrate that suppression of LGP2 leads to an enhanced IFNβ expression and increased killing of tumor cells.…”

mentioning

confidence: 99%

RIG-I–like receptor LGP2 protects tumor cells from ionizing radiation

Widau¹,

Parekh²,

Ranck³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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An siRNA screen targeting 89 IFN stimulated genes in 14 different cancer cell lines pointed to the RIG-I (retinoic acid inducible gene I)-like receptor Laboratory of Genetics and Physiology 2 (LGP2) as playing a key role in conferring tumor cell survival following cytotoxic stress induced by ionizing radiation (IR). Studies on the role of LGP2 revealed the following: (i) Depletion of LGP2 in three cancer cell lines resulted in a significant increase in cell death following IR, (ii) ectopic expression of LGP2 in cells increased resistance to IR, and (iii) IR enhanced LGP2 expression in three cell lines tested. Studies designed to define the mechanism by which LGP2 acts point to its role in regulation of IFNβ. Specifically (i) suppression of LGP2 leads to enhanced IFNβ, (ii) cytotoxic effects following IR correlated with expression of IFNβ inasmuch as inhibition of IFNβ by neutralizing antibody conferred resistance to cell death, and (iii) mouse embryonic fibroblasts from IFN receptor 1 knockout mice are radioresistant compared with wild-type mouse embryonic fibroblasts. The role of LGP2 in cancer may be inferred from cumulative data showing elevated levels of LGP2 in cancer cells are associated with more adverse clinical outcomes. Our results indicate that cytotoxic stress exemplified by IR induces IFNβ and enhances the expression of LGP2. Enhanced expression of LGP2 suppresses the IFN stimulated genes associated with cytotoxic stress by turning off the expression of IFNβ.innate immunity | cytoplasmic sensor | interferon beta | DHX58

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The RIG-I-like Receptor LGP2 Controls CD8+ T Cell Survival and Fitness

Cited by 110 publications

References 46 publications

The Essential, Nonredundant Roles of RIG-I and MDA5 in Detecting and Controlling West Nile Virus Infection

The Essential, Nonredundant Roles of RIG-I and MDA5 in Detecting and Controlling West Nile Virus Infection

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

RIG-I–like receptor LGP2 protects tumor cells from ionizing radiation

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