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

Widau, Ryan C.; Parekh, Akash D.; Ranck, M.C.; Golden, Daniel W.; Kumar, Kiran A; Sood, Ravi F.; Pitroda, Sean P.; Liao, Zhengkai; Huang, Xiaona; Darga, Thomas E.; Xu, David; Huang, Lei; Andrade, Jorge; Roizman, Bernard; Weichselbaum, Ralph R.; Khodarev, Nikolai N.

doi:10.1073/pnas.1323253111

Cited by 73 publications

(56 citation statements)

References 48 publications

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“…The type I IFN such as IFN-β is known to improve the response of tumor to ionizing radiation (22)(23)(24). For example, type I IFN affects the efficacy of radiotherapy through activation of immune cells (23).…”

Section: Discussionmentioning

confidence: 99%

Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer inï¿½vitro

et al. 2018

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Abstract. Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) are pattern-recognition receptors that recognize pathogen-associated molecular patterns and induce antiviral immune responses. Recent studies have demonstrated that RLR activation induces antitumor immunity and cytotoxicity against different types of cancer, including lung cancer. However a previous report has demonstrated that ionizing radiation exerts a limited effect on RLR in human monocytic cell-derived macrophages, suggesting that RLR agonists may be used as effective immunostimulants during radiation therapy. However, it is unclear whether ionizing radiation affects the cytotoxicity of RLR agonists against cancer cells. Therefore, in the present study the effects of cotreatment with ionizing radiation and RLR agonists on cytotoxicity against human non-small cell lung cancer cells A549 and H1299 was investigated. Treatment with RLR agonist poly(I:C)/LyoVec™ [poly(I:C)] exerted cytotoxic effects against human non-small cell lung cancer. The cytotoxic effects of poly(I:C) were enhanced by cotreatment with ionizing radiation, and poly(I:C) pretreatment resulted in the radiosensitization of non-small cell lung cancer. Furthermore, cotreatment of A549 and H1299 cells with poly(I:C) and ionizing radiation effectively induced apoptosis in a caspase-dependent manner compared with treatment with poly(I:C) or ionizing radiation alone. These results indicate that RLR agonists and ionizing radiation cotreatment effectively exert cytotoxic effects against human non-small cell lung cancer through caspase-mediated apoptosis.

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Section: Discussionmentioning

confidence: 99%

Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer inï¿½vitro

et al. 2018

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“…LGP2 has also been identified as a critical component of cancer cell resistance to ionizing radiation that is associated with clinical outcomes (73). It is unclear how these LGP2-driven phenomena relate to its roles in antiviral signaling, but these findings demonstrate the importance of further studies to fully understand the mechanisms of LGP2 function in a variety of contexts.…”

Section: Lgp2 As a Positive Regulatormentioning

confidence: 99%

MDA5 and LGP2: Accomplices and Antagonists of Antiviral Signal Transduction

Rodriguez

Bruns

Horvath

2014

J Virol

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Mammalian cells have the ability to recognize virus infection and mount a powerful antiviral transcriptional response that provides an initial barrier to replication and impacts both innate and adaptive immune responses. Retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) proteins mediate intracellular virus recognition and are activated by viral RNA ligands to induce antiviral signal transduction. While the mechanisms of RIG-I regulation are already well understood, less is known about the more enigmatic melanoma differentiation-associated 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2). Emerging evidence suggests that these two RLRs are intimately associated as both accomplices and antagonists of antiviral signal transduction.C ellular antiviral signaling is initiated following recognition of virus-encoded molecular signatures, often in the form of nucleic acids. Infection by RNA viruses results in cytosolic accumulation of double-stranded RNA (dsRNA) or otherwise chemically distinct, non-self RNA species. Sentry proteins in the cytoplasm recognize characteristics of non-self RNAs and can trigger downstream signal transduction pathways that culminate in activated antiviral transcription regulators (1-3). These factors accumulate in the nucleus, where they drive the expression of virus-induced genes, including the primary antiviral cytokine, beta interferon (IFN-␤), and diverse direct and indirect antiviral effectors (4).One group of intracellular responders, the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), includes the proteins RIG-I (5), melanoma differentiation-associated 5 (MDA5) (6), and laboratory of genetics and physiology 2 (LGP2) (7). Similar in structure and function, these proteins share significant sequence homologies that define them as the products of an evolutionarily conserved gene family (8) (Fig. 1A). The RLR proteins are thought to share the ability to detect molecular signatures of virus infection and activate antiviral signaling cascades, but they differ in both their RNA recognition capacities and signaling properties (9, 10). RIG-I, MDA5, and LGP2 share homologous DECH box helicase domain regions that have intrinsic dsRNA binding and ATP hydrolysis functions and a C-terminal domain that has been implicated in binding to RNA termini and autoregulation (11-13). RIG-I and MDA5 both have tandem N-terminal caspase activation and recruitment domain (CARD) motifs, protein interaction domains that mediate associations with upstream and downstream regulatory machinery. The CARDs are regulated by posttranslational modifications, including ubiquitination and phosphorylation (14-16). Current evidence indicates that RNA recognition by RIG-I and MDA5 is accompanied by CARD dephosphorylation, enabling their productive interaction with signaling machinery. Much of the knowledge of the RLR signaling pathway was developed by detailed study of RIG-I, the prototype RLR (17), and investigations of MDA5 have contributed greatly to a general paradigm for RLR signaling (Fig. 1...

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“…A number of experiments carried out in vivo and in vitro have revealed antithetic activities for LGP2 as both an activator and an inhibitor of RLR-mediated antiviral signaling [47, 65], and three independent LGP2 knockout mouse lines were reported with distinct but overlapping phenotypes [11, 66–70]. LGP2 can mediate cellular responses related to viral RNA recognition and antiviral signaling, and participates in antiviral T cell expansion [69], responses triggered by cytosolic dsDNA [71], and cancer cell resistance to ionizing radiation [72]. …”

Section: Lgp2mentioning

confidence: 99%

Antiviral RNA recognition and assembly by RLR family innate immune sensors

Bruns

Horvath

2014

Cytokine & Growth Factor Reviews

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Virus-encoded molecular signatures, such as cytosolic double-stranded or otherwise biochemically distinct RNA species, trigger cellular antiviral signaling. Cytoplasmic proteins recognize these non-self RNAs and activate signal transduction pathways that drive the expression of virus-induced genes, including the primary antiviral cytokine, IFNβ, and diverse direct and indirect antiviral effectors [1–4]. One important group of cytosolic RNA sensors known as the RIG-I like receptors (RLRs) is comprised of three proteins that are similar in structure and function. The RLR proteins, RIG-I, MDA5, and LGP2, share the ability to recognize nucleic acid signatures produced by virus infections and activate antiviral signaling. Emerging evidence indicates that RNA detection by RLRs culminates in the assembly of dynamic multimeric ribonucleoprotein (RNP) complexes. These RNPs can act as signaling platforms that are capable of propagating and amplifying antiviral signaling responses. Despite their common domain structures and similar abilities to induce antiviral responses, the RLRs differ in their enzymatic properties, their intrinsic abilities to recognize RNA, and their ability to assemble into filamentous complexes. This molecular specialization has enabled the RLRs to recognize and respond to diverse virus infections, and to mediate both unique and overlapping functions in immune regulation [5, 6].

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

Cited by 73 publications

References 48 publications

Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer inï¿½vitro

Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer inï¿½vitro

MDA5 and LGP2: Accomplices and Antagonists of Antiviral Signal Transduction

Antiviral RNA recognition and assembly by RLR family innate immune sensors

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