Phosphorylation of RIG-I by Casein Kinase II Inhibits Its Antiviral Response

Sun, Zhiguo; Ren, Hongwei; Liu, Yan; Teeling, Jessica L.; Gu, Jun

doi:10.1128/jvi.01734-10

Cited by 100 publications

(80 citation statements)

References 26 publications

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“…This may be due to their different localization in cells or their expression specificity and abundance in various tissues (10). It has been reported that CK2 can phosphorylate RIG-I and inhibits its antiviral response (29), but in our experiments we did not observe an obvious inhibition effect of CK2a2 on flu RNAmediated IFN-b activation, which may due to different CK2 isoforms exhibiting diverse biological function. Whether other casein kinases are involved in the RIG-I pathway needs further elucidated.…”

Section: Discussioncontrasting

confidence: 71%

Casein Kinase 1γ1 Inhibits the RIG-I/TLR Signaling Pathway through Phosphorylating p65 and Promoting Its Degradation

Wang

Tong

et al. 2014

The Journal of Immunology

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The casein kinase 1 (CK1) plays an important role in various biological processes by phosphorylating its target proteins. In this study, we demonstrate that CK1γ1 inhibits RNA virus–mediated activation of retinoic acid–inducible gene I (RIG-I) signaling by affecting the stability of NF-κB subunit p65. First, we found that ectopic expression of CK1γ1 inhibits RIG-I pathway–mediated activation of IFN-β, whereas knockdown of CK1γ1 potentiates the activation of IFN-β and NF-κB induced by Sendai virus (SeV). We then revealed that CK1γ1 interacts with p65 and specifically enhances its phosphorylation at Ser536 induced by SeV. By using an in vitro kinase assay, we confirmed that CK1γ1 can phosphorylate p65 at Ser536. We also showed that the kinase dead mutants CK1γ1K73A and CK1γ1N169A did not inhibit SeV-induced activation of IFN-β and NF-κB, suggesting that the kinase activity of CK1γ1 is critical for its inhibitory effect on RIG-I signaling. Additionally, we found that CK1γ1 also has the similar effect on TLR signaling. Further analysis indicated that CK1γ1 phosphorylates p65 and consequently promotes its degradation by ubiquitin E3 ligases CUL2 and COMMD1. These results revealed a novel negative regulatory manner of CK1γ1 on innate immune signaling.

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Section: Discussioncontrasting

confidence: 71%

Casein Kinase 1γ1 Inhibits the RIG-I/TLR Signaling Pathway through Phosphorylating p65 and Promoting Its Degradation

Wang

Tong

et al. 2014

The Journal of Immunology

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“…The autophagy conjugate Atg5-Atg12, ISG15, and SUMOylation were reported to inhibit or improve RIG-I signaling (33)(34)(35). RIG-I serine 8 phosphorylation induced by protein kinase C ␣/␤ (PKC-␣/␤) and the C-terminal repressor domain (RD) phosphorylated by casein kinase II are also a critical regulatory mechanism (36)(37)(38). Recent research has shown that PP1␣ and PP1␥ are the primary phosphatases responsible for RIG-I dephosphorylation and lead to its activation (39).…”

Section: Discussionmentioning

confidence: 99%

Negative Regulation of RIG-I-Mediated Innate Antiviral Signaling by SEC14L1

et al. 2013

J Virol

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Retinoic acid-inducible gene I (RIG-I) is a key sensor for recognizing nucleic acids derived from RNA viruses and triggers beta interferon (IFN-β) production. Because of its important role in antiviral innate immunity, the activity of RIG-I must be tightly controlled. Here, we used yeast two-hybrid screening to identify a SEC14 family member, SEC14L1, as a RIG-I-associated negative regulator. Transfected SEC14L1 interacted with RIG-I, and endogenous SEC14L1 associated with RIG-I in a viral infection-inducible manner. Overexpression of SEC14L1 inhibited transcriptional activity of the IFN-β promoter induced by RIG-I but not TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3). Knockdown of endogenous SEC14L1 in both HEK293T cells and HT1080 cells potentiated RIG-I and Sendai virus-triggered IFN-β production as well as attenuated the replication of Newcastle disease virus. SEC14L1 interacted with the N-terminal domain of RIG-I (RIG-I caspase activation and recruitment domain [RIG-I-CARD]) and competed with VISA/MAVS/IPS-1/Cardif for RIG-I-CARD binding. Domain mapping further indicated that the PRELI-MSF1 and CRAL-TRIO domains but not the GOLD domain of SEC14L1 are required for interaction and inhibitory function. These findings suggest that SEC14L1 functions as a novel negative regulator of RIG-I-mediated antiviral signaling by preventing RIG-I interaction with the downstream effector.

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“…An in vitro GST pulldown assay was performed as previously described (41). Briefly, purified GST-tagged RTA proteins (5 g) expressed in bacteria were incubated with 10 l glutathione Sepharose 4B for 4 h at 4°C, followed by the addition of 2 g purified His-tagged HLA-DR␣ or His-tagged HLA-DR␤ protein, and then incubated at 4°C overnight.…”

Section: Methodsmentioning

confidence: 99%

Major Histocompatibility Complex Class II HLA-DRα Is Downregulated by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Lytic Transactivator RTA and MARCH8

Sun

Jha

Pei

2016

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) maintains two modes of life cycle, the latent and lytic phases. To evade the attack of the cell host's immune system, KSHV switches from the lytic to the latent phase, a phase in which only a few of viral proteins are expressed. The mechanism by which KSHV evades the attack of the immune system and establishes latency has not been fully understood. Major histocompatibility complex class II (MHC-II) molecules are key components of the immune system defense mechanism against viral infections. Here we report that HLA-DR␣, a member of the MHC-II molecules, was downregulated by the replication and transcription activator (RTA) protein encoded by KSHV ORF50, an important regulator of the viral life cycle. RTA not only downregulated HLA-DR␣ at the protein level through direct binding and degradation through the proteasome pathway but also indirectly downregulated the protein level of HLA-DR␣ by enhancing the expression of MARCH8, a member of the membrane-associated RING-CH (MARCH) proteins. Our findings indicate that KSHV RTA facilitates evasion of the virus from the immune system through manipulation of HLA-DR␣. IMPORTANCEKaposi's sarcoma-associated herpesvirus (KSHV) has a causal role in a number of human cancers, and its persistence in infected cells is controlled by the host's immune system. The mechanism by which KSHV evades an attack by the immune system has not been well understood. This work represents studies which identify a novel mechanism by which the virus can facilitate evasion of an immune system. We now show that RTA, the replication and transcription activator encoded by KSHV (ORF50), can function as an E3 ligase to degrade HLA-DR␣. It can directly bind and induce degradation of HLA-DR␣ through the ubiquitin-proteasome degradation pathway. In addition to the direct regulation of HLA-DR␣, RTA can also indirectly downregulate the level of HLA-DR␣ protein by upregulating transcription of MARCH8. Increased MARCH8 results in the downregulation of HLA-DR␣. Furthermore, we also demonstrate that expression of HLA-DR␣ was impaired in KSHV de novo infection. K aposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV-8), is a Rhadinovirus belonging to the Gammaherpesvirinae subfamily. It was discovered in Kaposi's sarcoma (KS) lesions and is also associated with primary effusion lymphoma (PEL) and multicentric Castleman's disease (1-3). Almost 20% of all human malignancies are caused by viruses (4). The majority of infected individuals do not develop tumors, although immunosuppressive conditions like AIDS and organ transplantation can dramatically increase the risk of developing a malignancy. This suggests an active role for the host immune system in controlling KSHV infections (5, 6). During its coevolution with the host, KSHV hijacks and manipulates many of the host machineries to override the host immune surveillance (7,8). The host ubiquitin system has fundamental roles in regulating cellular events, like protein degradation and...

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Phosphorylation of RIG-I by Casein Kinase II Inhibits Its Antiviral Response

Cited by 100 publications

References 26 publications

Casein Kinase 1γ1 Inhibits the RIG-I/TLR Signaling Pathway through Phosphorylating p65 and Promoting Its Degradation

Casein Kinase 1γ1 Inhibits the RIG-I/TLR Signaling Pathway through Phosphorylating p65 and Promoting Its Degradation

Negative Regulation of RIG-I-Mediated Innate Antiviral Signaling by SEC14L1

Major Histocompatibility Complex Class II HLA-DRα Is Downregulated by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Lytic Transactivator RTA and MARCH8

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