Loss of RIG-I leads to a functional replacement with MDA5 in the Chinese tree shrew

Xu, Ling; Yu, Dandan; Yu, Fan; Li, Peng; Wu, Yong; Yao, Yong‐Gang

doi:10.1073/pnas.1604939113

Cited by 75 publications

(73 citation statements)

References 44 publications

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“…In a comparable example, rare nonsynonymous variants in TYK2, a known primary immunodeficiency gene, were shown to be protective against rheumatoid arthritis (31). Incomplete penetrance, on the other hand, could be due to modulating effects of environmental or genetic factors, like compensatory mutations, or to functional redundancy in innate immune response to RNA viruses (32,33). This hypothesis is in line with several recent publications (34)(35)(36)(37), which suggest that incomplete penetrance and genetic heterogeneity are likely to be the rule rather than the exception in severe clinical presentations of infectious diseases.…”

Section: Discussionmentioning

confidence: 99%

Severe viral respiratory infections in children with IFIH1 loss-of-function mutations

Asgari

Schlapbach

Anchisi

et al. 2017

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

116

127

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Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins are unable to induce IFN-β, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that IFIH1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses. V iral respiratory tract infections are the most common childhood infections worldwide, with close to 100% of children being infected during the first years of life. Whereas the vast majority of viral respiratory infections are mild and self-limiting, more severe disease leads to the hospitalization of about 3% of individuals in each birth cohort (1). In-hospital mortality rates are limited to <1% with intensive care support; still these infections account for 21% of childhood mortality worldwide (2, 3). The main viral pathogens causing lower respiratory tract infections are human respiratory syncytial virus (RSV), enteroviruses [including human rhinoviruses (HRV)], adenoviruses, human metapneumovirus, coronavirus, influenza, and parainfluenza viruses, with RSV being responsible for the majority of the hospitalized pediatric cases (4, 5).A number of risk factors including socioeconomic and environmental influences, preterm birth, chronic diseases, and immunosuppression are associated with more severe clinical presentation (6). However, ∼1 out of 1,000 children without any known risk factor will require intensive care support due to life-threatening manifestations of common viral respiratory infections. In the absence of established differences in pathogen virulence, we hypothesized that human genetic variation contributes to unusual susceptibility to severe disease due to common viruses. Supporting evidence is provided by a recent study, which showed that rare variants in IRF7 resulted in life-threatening influenza in an otherwise healthy child (7).We combined exome sequencing, transcriptomic analysis, and in vitro functional testing to identify and characterize potentially causal genetic variants in a prospective cohort of previously healthy children requiring intensive care support for common respiratory viral infections. We report the identification of a pathogen-restricted immunodeficiency due to loss-of-function variants in IFIH1, which result in defective innate recognition of RNA viruses, preventing the activation of an efficie...

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Section: Discussionmentioning

confidence: 99%

Severe viral respiratory infections in children with IFIH1 loss-of-function mutations

Asgari

Schlapbach

Anchisi

et al. 2017

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

116

127

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“…However, in some RIG-I-null species, such as chicken and Chinese tree shrew, MITA can interact with MDA5 to mediate the corresponding signaling. Knockdown of MITA inhibits MDA5-mediated IFN-β activation (9, 19). Therefore, experimental evidence needs to be proposed to identify whether MITA is essential for MDA5 signaling pathway in RIG-I-existed species and compare the difference between RIG-I- and MDA5-mediated MITA downstream signals.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, LGP2 can inhibit antiviral signaling by competing with the kinase IKKi for a common interaction site on IPS-1 (15). However, other groups support the positive role of LGP2 in antiviral responses (16–19). Direct evidence suggests that LGP2 assists MDA5–RNA interaction and regulates MDA5 filament assembly to enhance MDA5-mediated antiviral signaling (16).…”

Section: Introductionmentioning

confidence: 99%

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Grass Carp Laboratory of Genetics and Physiology 2 Serves As a Negative Regulator in Retinoic Acid-Inducible Gene I- and Melanoma Differentiation-Associated Gene 5-Mediated Antiviral Signaling in Resting State and Early Stage of Grass Carp Reovirus Infection

et al. 2017

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Laboratory of genetics and physiology 2 (LGP2) is a key component of RIG-I-like receptors (RLRs). However, the lack of the caspase recruitment domains (CARDs) results in its controversial functional performance as a negative or positive regulator in antiviral responses. Especially, no sufficient evidence uncovers the functional mechanisms of LGP2 in RLR signaling pathways in teleost. Here, negative regulation mechanism of LGP2 in certain situations in retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5)-mediated antiviral responses was identified in Ctenopharyngodon idella kidney cells. LGP2 overexpression inhibits synthesis and phosphorylation of interferon regulatory factor 3/7 (IRF3/7), and mRNA levels and promoter activities of IFNs and NF-κBs in resting state and early phase of grass carp reovirus (GCRV) infection. Knockdown of LGP2 obtains opposite effects. Luciferase report assay indicates that LGP2 works at the upstream of RIG-I and MDA5. LGP2 binds to RIG-I and MDA5 with diverse domain preference and which is independent of GCRV infection. Furthermore, LGP2 restrains K63-linked ubiquitination of RIG-I and MDA5 in various degrees. These differences result in disparate repressive mechanisms of LGP2 to RIG-I- and MDA5-mediated signal activations of IFN-β promoter stimulator 1 and mediator of IRF3 activation. Interestingly, LGP2 also inhibits K48-linked RIG-I and MDA5 ubiquitination to suppress proteins degradation, which guarantees the basal protein levels for subsequently rapid signal activation. All these results reveal a mechanism that LGP2 functions as a suppressor in RLR signaling pathways to maintain cellular homeostasis in resting state and early phase during GCRV infection.

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“…However, work in chickens infected with the HPAIV H5N1 demonstrated rapid induction of IFNα transcripts and protein indicating that alternative pathways such as the MDA-5 and/or the TLR pathways may account for the response [20]. Interestingly, such a loss in the family of RIG-I like receptors was not only found in birds but also in mammals as recently reported for RIG-I in the Chinese tree shrew [21]. …”

Section: Introductionmentioning

confidence: 89%

Tissue and time specific expression pattern of interferon regulated genes in the chicken

Röll

Härtle²,

Lütteke

et al. 2017

BMC Genomics

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BackgroundType I interferons are major players against viral infections and mediate their function by the induction of Interferon regulated genes (IRGs). Recently, it became obvious that these cytokines have a multitude of additional functions. Due to the unique features of the chickens’ immune system, available data from mouse models are not easily transferable; hence we performed an extensive analysis of chicken IRGs.ResultsA broad database search for homologues to described mammalian IRGs (common IRGs, cIRGs) was combined with a transcriptome analysis of spleen and lung at different time points after application of IFNα. To apply physiological amounts of IFN, half-life of IFN in the chicken was determined. Interestingly, the calculated 36 min are considerably shorter than the ones obtained for human and mouse. Microarray analysis revealed many additional IRGs (newly identified IRGs; nIRGs) and network analysis for selected IRGs showed a broad interaction of nIRGs among each other and with cIRGs. We found that IRGs exhibit a highly tissue and time specific expression pattern as expression quality and quantity differed strongly between spleen and lung and over time. While in the spleen for many affected genes changes in RNA abundance peaked already after 3 h, an increasing or plateau-like regulation after 3, 6 and 9 h was observed in the lung.ConclusionsThe induction or suppression of IRGs in chickens is both tissue and time specific and beside known antiviral mechanisms type I IFN induces many additional cellular functions. We confirmed many known IRGs and established a multitude of so far undescribed ones, thus providing a large database for future research on antiviral mechanisms and additional IFN functions in non-mammalian species.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3641-6) contains supplementary material, which is available to authorized users.

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Loss of RIG-I leads to a functional replacement with MDA5 in the Chinese tree shrew

Cited by 75 publications

References 44 publications

Severe viral respiratory infections in children with IFIH1 loss-of-function mutations

Severe viral respiratory infections in children with IFIH1 loss-of-function mutations

Grass Carp Laboratory of Genetics and Physiology 2 Serves As a Negative Regulator in Retinoic Acid-Inducible Gene I- and Melanoma Differentiation-Associated Gene 5-Mediated Antiviral Signaling in Resting State and Early Stage of Grass Carp Reovirus Infection

Tissue and time specific expression pattern of interferon regulated genes in the chicken

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