Threonine 80 phosphorylation of non-structural protein 1 regulates the replication of influenza A virus by reducing the binding affinity with RIG-I

Zheng, Wei; Cao, Shuaishuai; Chen, Can; Li, Jing; Zhang, Shuang; Jiang, Jingwen; Niu, Yange; Fan, Wenhui; Li, Yun; Bi, Yuhai; Gao, George F.; Sun, Lei; Liu, Wenjun

doi:10.1111/cmi.12643

Cited by 23 publications

(17 citation statements)

References 45 publications

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“…Conversely, phosphorylation of NS1 at Thr49 was recently identified as impairing the NS1-TRIM25 interaction, thereby suppressing its antagonistic activity of RIG-I signaling (102). Phosphorylation of another site on NS1, Thr80, has also been reported to disrupt NS1 binding affinity with RIG-I (103). Similar to IAV, the IBV non-structural NS protein (NS1-B) has recently been described as inhibiting RIG-I ubiquitination, which involves TRIM25-NS1 C-terminal effector domain interaction and the RIG-I/TRIM25/ NS1-B complex formation (104).…”

Section: Modulation Of the Ptmsmentioning

confidence: 99%

Host and Viral Modulation of RIG-I-Mediated Antiviral Immunity

2017

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Innate immunity is the first line of defense against invading pathogens. Rapid and efficient detection of pathogen-associated molecular patterns via pattern-recognition receptors is essential for the host to mount defensive and protective responses. Retinoic acid-inducible gene-I (RIG-I) is critical in triggering antiviral and inflammatory responses for the control of viral replication in response to cytoplasmic virus-specific RNA structures. Upon viral RNA recognition, RIG-I recruits the mitochondrial adaptor protein mitochondrial antiviral signaling protein, which leads to a signaling cascade that coordinates the induction of type I interferons (IFNs), as well as a large variety of antiviral interferon-stimulated genes. The RIG-I activation is tightly regulated via various posttranslational modifications for the prevention of aberrant innate immune signaling. By contrast, viruses have evolved mechanisms of evasion, such as sequestrating viral structures from RIG-I detections and targeting receptor or signaling molecules for degradation. These virus–host interactions have broadened our understanding of viral pathogenesis and provided insights into the function of the RIG-I pathway. In this review, we summarize the recent advances regarding RIG-I pathogen recognition and signaling transduction, cell-intrinsic control of RIG-I activation, and the viral antagonism of RIG-I signaling.

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Section: Modulation Of the Ptmsmentioning

confidence: 99%

Host and Viral Modulation of RIG-I-Mediated Antiviral Immunity

2017

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“…Phosphorylation of NP contributes to its nuclearcytoplasmic shuttling, self-oligomerization, and vRNP activity, thereby affecting viral growth (20)(21)(22)(23)(24). Phosphorylation of NS1 regulates its dimerization and nuclear localization (20), and phosphorylation of threonine at residues 49 and 80 of NS1 suppresses its interferon-antagonistic activity and binding affinity with RIG-I, respectively, leading to attenuation of virus replication (25,26). Phosphorylation of the nuclear export The recombinant viruses possessing wild-type CM2, CM2-S78A, CM2-S103A, or CM2-S78/103A were generated by reverse genetics as described in Materials and Methods and designated rWT, rS78A, rS103A, or rS78/103A, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…The present study was approved by the Safety Committee for Gene Recombination Experiments of Yamagata University (no. [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41].…”

Section: Methodsmentioning

confidence: 99%

Effect of Phosphorylation of CM2 Protein on Influenza C Virus Replication

Goto

Shimotai

Matsuzaki

et al. 2017

J Virol

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CM2 is the second membrane protein of the influenza C virus and has been demonstrated to play a role in the uncoating and genome packaging processes in influenza C virus replication. Although the effects of N-linked glycosylation, disulfide-linked oligomerization, and palmitoylation of CM2 on virus replication have been analyzed, the effect of the phosphorylation of CM2 on virus replication remains to be determined. In this study, a phosphorylation site(s) at residue 78 and/or 103 of CM2 was replaced with an alanine residue(s), and the effects of the loss of phosphorylation on influenza C virus replication were analyzed. No significant differences were observed in the packaging of the reporter gene between influenza C virus-like particles (VLPs) produced from 293T cells expressing wild-type CM2 and those from the cells expressing the CM2 mutants lacking the phosphorylation site(s). Reporter gene expression in HMV-II cells infected with VLPs containing the CM2 mutants was inhibited in comparison with that in cells infected with wild-type VLPs. The virus production of the recombinant influenza C virus possessing CM2 mutants containing a serine-to-alanine change at residue 78 was significantly lower than that of wild-type recombinant influenza C virus. Furthermore, the virus growth of the recombinant viruses possessing CM2 with a serine-to-aspartic acid change at position 78, to mimic constitutive phosphorylation, was virtually identical to that of the wild-type virus. These results suggest that phosphorylation of CM2 plays a role in efficient virus replication, probably through the addition of a negative charge to the Ser78 phosphorylation site. It is well-known that many host and viral proteins are posttranslationally modified by phosphorylation, which plays a role in the functions of these proteins. In influenza A and B viruses, phosphorylation of viral proteins NP, M1, NS1, and the nuclear export protein (NEP), which are not integrated into the membranes, affects the functions of these proteins, thereby affecting virus replication. However, it was reported that phosphorylation of the influenza A virus M2 ion channel protein, which is integrated into the membrane, has no effect on virus replication or We previously demonstrated that the influenza C virus CM2 ion channel protein is modified by N-glycosylation, oligomerization, palmitoylation, and phosphorylation and have analyzed the effects of these modifications, except phosphorylation, on virus replication. This is the first report demonstrating that phosphorylation of the influenza C virus CM2 ion channel protein, unlike that of the influenza A virus M2 protein, plays a role in virus replication.

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“…Recent studies showed that phosphorylation may also occur at Thr49, which inhibits NS1's association to TRIM25 and decreases NS1 ability to interfere with the IFN cascade [58]. Another study showed that Thr80 phosphorylation reduces interaction with retinoic acid-inducible gene 1-like receptor dsRNA helicase enzyme (RIG-I) hence making NS1 unable to inhibit the IFN cascade [59]. Some H5N1 subtype strains display a mutation in Asp92 to Glu92 which reduces the strength of the hydrogen bonding interaction between Glu92 Ser195 and Thr197.…”

Section: Post-translational Modifications: Phosphorylation Sumoylatimentioning

confidence: 99%

The Central Role of Non-Structural Protein 1 (NS1) in Influenza Biology and Infection

Rosário‐Ferreira

Preto

Melo

et al. 2020

IJMS

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Influenza (flu) is a contagious viral disease, which targets the human respiratory tract and spreads throughout the world each year. Every year, influenza infects around 10% of the world population and between 290,000 and 650,000 people die from it according to the World Health Organization (WHO). Influenza viruses belong to the Orthomyxoviridae family and have a negative sense eight-segment single-stranded RNA genome that encodes 11 different proteins. The only control over influenza seasonal epidemic outbreaks around the world are vaccines, annually updated according to viral strains in circulation, but, because of high rates of mutation and recurrent genetic assortment, new viral strains of influenza are constantly emerging, increasing the likelihood of pandemics. Vaccination effectiveness is limited, calling for new preventive and therapeutic approaches and a better understanding of the virus–host interactions. In particular, grasping the role of influenza non-structural protein 1 (NS1) and related known interactions in the host cell is pivotal to better understand the mechanisms of virus infection and replication, and thus propose more effective antiviral approaches. In this review, we assess the structure of NS1, its dynamics, and multiple functions and interactions, to highlight the central role of this protein in viral biology and its potential use as an effective therapeutic target to tackle seasonal and pandemic influenza.

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Threonine 80 phosphorylation of non-structural protein 1 regulates the replication of influenza A virus by reducing the binding affinity with RIG-I

Cited by 23 publications

References 45 publications

Host and Viral Modulation of RIG-I-Mediated Antiviral Immunity

Host and Viral Modulation of RIG-I-Mediated Antiviral Immunity

Effect of Phosphorylation of CM2 Protein on Influenza C Virus Replication

The Central Role of Non-Structural Protein 1 (NS1) in Influenza Biology and Infection

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