RSV replication is attenuated by counteracting expression of the suppressor of cytokine signaling (SOCS) molecules

Hashimoto, Koichi; Ishibashi, Keiichiro; Ishioka, Ken; Zhao, Dongchi; Sato, Masatoki; Ohara, Shinichiro; Abe, Yusaku; Kawasaki, Yukihiko; Sato, Yuka; Yokota, Shinichi; Fujii, Nobuhiro; Peebles, R. Stokes; Hosoya, Mitsuaki; Suzutani, Tatsuo

doi:10.1016/j.virol.2009.06.026

Cited by 39 publications

(41 citation statements)

References 51 publications

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“…The siRNA sequences were: siNS1 gene 5′-GUGAUUCAACAAUGACCAAdTdT-3′; siSOCS1 gene 5′-CGCCGUGCACGCAGCAUUAAC-3′[11]; siTLR3 5′- GCUCGAUCUUUCCUACAACAAdTdT-3′; siRIG-I 5′- GCAAGAUCUUACUCAGAGAUUdTdT-3′. The siRNA inhibition efficiency was determined with real-time polymerase chain reaction (PCR).…”

Section: Methodsmentioning

confidence: 99%

“…In vitro, RSV induces a lower level of interferon (IFN) and interferes with type I IFN signaling by degrading the signal transducer and activator of transcription (STAT)2 protein and inhibiting STAT2 phosphorylation [9,10,11,12]. Recombinant RSV mutants lacking NS1 and NS2 cause marked production of host IFN-α and -β, highlighting the importance of these proteins in resisting the innate antiviral response [7,8].…”

Section: Introductionmentioning

confidence: 99%

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Respiratory Syncytial Virus NS1 Protein Degrades STAT2 by Inducing SOCS1 Expression

Xu¹,

Zheng²,

Zheng³

et al. 2014

Intervirology

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Objectives: Respiratory syncytial virus (RSV) nonstructural protein NS1 (NS1) has been shown to block interferon (IFN)-inducible antiviral signaling. The suppressor of cytokine signaling (SOCS) gene family could utilize a feedback loop to block the activation of the JAK/STAT signaling pathway, further inhibiting the activation of host type I IFN. We evaluated the role of the SOCS1 and SOCS3 genes in this antiviral mechanism. Material and Methods: A humanized stable NS1 (rich in GC)-expressing plasmid was constructed, and A549 cells were transfected with it. Expression of the SOCS1, SOCS3, RIG-I, and TLR3 mRNAs was measured with real-time PCR. STAT2 and pSTAT2 expression was determined with Western blotting. Results: RSV NS1 upregulated SOCS1 mRNA expression 30-fold increase compared with the baseline level in very early phase (p < 0.01), and silence of RIG-I or TLR3 mRNA did not affect NS1-induced SOCS1 expression. NS1 inhibited IFN-α-induced STAT2 phosphorylation and degraded STAT2 in a time-dependent manner compared with the empty-vector control (p < 0.05). Conclusion: RSV NS1 upregulates SOCS1 expression in a RIG-I- and TLR3-independent pathway, to inhibit STAT2 phosphorylation.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Respiratory Syncytial Virus NS1 Protein Degrades STAT2 by Inducing SOCS1 Expression

Xu¹,

Zheng²,

Zheng³

et al. 2014

Intervirology

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“…Influenza A virus (47,52), RSV (24,79), and HBV (30,72) (Table 1) are just a few examples of viruses that benefit in this manner by exploiting SOCS protein function. It is likely that the discovery of others will soon follow.…”

Section: Virally Exploited Functions Of Socs Proteinsmentioning

confidence: 99%

“…While RSV can induce the expression of SOCS1, SOCS3, and CIS and establish a successful infection in macrophages (phorbol myristate acetate [PMA]-differentiated U937 cells), it is not capable of SOCS expression or infection in monocytes (undifferentiated U937 cells) (79). A subsequent report showed that knockdown of any of these SOCS proteins in cells susceptible to infection resulted in an increase in STAT1/2 phosphorylation and expression of the IFN-induced antiviral target gene OAS, as well as a correlating decrease in RSV replication (24). These studies suggest that SOCS expression contributes to the differences in permissiveness to RSV infection that accompany the cellular differentiation state of macrophages.…”

Section: Effects Of Socs Expression On Viral Diseasementioning

confidence: 99%

Viral Exploitation of Host SOCS Protein Functions

Akhtar

Benveniste

2011

J Virol

107

100

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Over the past decade, a family of host proteins known as suppressors of cytokine signaling (SOCS) have emerged as frequent targets of viral exploitation. Under physiologic circumstances, SOCS proteins negatively regulate inflammatory signaling pathways by facilitating ubiquitination and proteosomal degradation of pathway machinery. Their expression is tightly regulated to prevent excessive inflammation while maintaining protective antipathogenic responses. Numerous viruses, however, have developed mechanisms to induce robust host SOCS protein expression following infection, essentially "hijacking" SOCS function to promote virus survival. To date, SOCS proteins have been shown to inhibit protective antiviral signaling pathways, allowing viruses to evade the host immune response, and to ubiquitinate viral proteins, facilitating intracellular viral trafficking and progeny virus assembly. Importantly, manipulation of SOCS proteins not only facilitates progression of the viral life cycle but also powerfully shapes the presentation of viral disease. SOCS proteins can define host susceptibility to infection, contribute to peripheral disease manifestations such as immune dysfunction and cancer, and even modify the efficacy of therapeutic interventions. Looking toward the future, it is clear that a better understanding of the role of SOCS proteins in viral diseases will be essential in our struggle to modulate and even eliminate the pathogenic effects of viruses on the host.

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“…Other studies have demonstrated that mice lacking both SOCS1 and IFN-γ can be cured of otherwise lethal melanoma tumors through exogenous administration of IFN-α Guenterberg, K. D. et al 2011). Finally, studies from Hashimoto et al have demonstrated that silencing SOCS1 in macrophages enhances the survival of mice bearing B16 melanoma tumors (Hashimoto, K. et al 2009). Together these data suggest that SOCS proteins within the adaptive immune system play an instrumental role in regulating the anti-tumor response against melanoma.…”

Section: Negative Regulation Of Jak-stat Signal Transductionmentioning

confidence: 99%