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Viral induction of AID is independent of the interferon and the Toll-like receptor signaling pathways but requires NF-kappaB.

Gourzi P, Leonova T, Papavasiliou FN - J. Exp. Med. (2007)

Bottom Line: Here we show that AID is not an interferon responsive gene and abrogation of Toll-like receptor signaling does not diminish the AID response.However, we found that NF-kappaB was required for expression of virally induced AID.Since NF-kappaB binds and activates the AID promoter, these results mechanistically link viral infection with AID transcription.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Lymphocyte Biology, The Rockefeller University, New York, NY 10021, USA.

ABSTRACT
Activation-induced cytidine deaminase (AID) is expressed in germinal centers of lymphoid organs during immunoglobulin diversification, in bone marrow B cells after infection with Abelson murine leukemia retrovirus (Ab-MLV), and in human B cells after infection by hepatitis C virus. To understand how viruses signal AID induction in the host we asked whether the AID response was abrogated in cells deficient in the interferon pathway or in signaling via the Toll-like receptors. Here we show that AID is not an interferon responsive gene and abrogation of Toll-like receptor signaling does not diminish the AID response. However, we found that NF-kappaB was required for expression of virally induced AID. Since NF-kappaB binds and activates the AID promoter, these results mechanistically link viral infection with AID transcription. Thus, induction of AID by viruses could be the result of several signaling pathways that culminate in NF-kappaB activation, underscoring the versatility of this host defense program.

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NF-κB is required for expression of virally induced AID. (A) Bone marrow cells from NF-κB (p50)−/− mice cannot induce AID expression upon infection with Ab-MLV. (B) NF-κB (p50)−/− splenic B cells are defective in CSR. Levels of CSR to IgG1 and IgG3 are shown 72 h after stimulation with LPS and IL-4 or CD40 and IL-4. (C) NF-κB is required for optimal AID expression in switching B cells.
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fig4: NF-κB is required for expression of virally induced AID. (A) Bone marrow cells from NF-κB (p50)−/− mice cannot induce AID expression upon infection with Ab-MLV. (B) NF-κB (p50)−/− splenic B cells are defective in CSR. Levels of CSR to IgG1 and IgG3 are shown 72 h after stimulation with LPS and IL-4 or CD40 and IL-4. (C) NF-κB is required for optimal AID expression in switching B cells.

Mentions: NF-κB is required for the Ig diversification program (18) and can be activated by several overlapping though distinct signaling pathways, many of which are activated by viral infection (25). To determine whether virally induced AID expression requires NF-κB, we used Ab-MLV to infect bone marrow cells from mice deficient in the p50 subunit of the NF-κB heterodimer. We found that such NF- κB–deficient B cells were completely unable to up-regulate AID expression (Fig. 4 A). In addition, such cells were more susceptible to viral transformation (26 and unpublished data). Thus, the host response of NF-κB–deficient B cells to Ab-MLV infection and transformation closely parallels the one reported for AID-deficient B cells (20), suggesting a genetic link between the two.


Viral induction of AID is independent of the interferon and the Toll-like receptor signaling pathways but requires NF-kappaB.

Gourzi P, Leonova T, Papavasiliou FN - J. Exp. Med. (2007)

NF-κB is required for expression of virally induced AID. (A) Bone marrow cells from NF-κB (p50)−/− mice cannot induce AID expression upon infection with Ab-MLV. (B) NF-κB (p50)−/− splenic B cells are defective in CSR. Levels of CSR to IgG1 and IgG3 are shown 72 h after stimulation with LPS and IL-4 or CD40 and IL-4. (C) NF-κB is required for optimal AID expression in switching B cells.
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Related In: Results  -  Collection

Show All Figures
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fig4: NF-κB is required for expression of virally induced AID. (A) Bone marrow cells from NF-κB (p50)−/− mice cannot induce AID expression upon infection with Ab-MLV. (B) NF-κB (p50)−/− splenic B cells are defective in CSR. Levels of CSR to IgG1 and IgG3 are shown 72 h after stimulation with LPS and IL-4 or CD40 and IL-4. (C) NF-κB is required for optimal AID expression in switching B cells.
Mentions: NF-κB is required for the Ig diversification program (18) and can be activated by several overlapping though distinct signaling pathways, many of which are activated by viral infection (25). To determine whether virally induced AID expression requires NF-κB, we used Ab-MLV to infect bone marrow cells from mice deficient in the p50 subunit of the NF-κB heterodimer. We found that such NF- κB–deficient B cells were completely unable to up-regulate AID expression (Fig. 4 A). In addition, such cells were more susceptible to viral transformation (26 and unpublished data). Thus, the host response of NF-κB–deficient B cells to Ab-MLV infection and transformation closely parallels the one reported for AID-deficient B cells (20), suggesting a genetic link between the two.

Bottom Line: Here we show that AID is not an interferon responsive gene and abrogation of Toll-like receptor signaling does not diminish the AID response.However, we found that NF-kappaB was required for expression of virally induced AID.Since NF-kappaB binds and activates the AID promoter, these results mechanistically link viral infection with AID transcription.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Lymphocyte Biology, The Rockefeller University, New York, NY 10021, USA.

ABSTRACT
Activation-induced cytidine deaminase (AID) is expressed in germinal centers of lymphoid organs during immunoglobulin diversification, in bone marrow B cells after infection with Abelson murine leukemia retrovirus (Ab-MLV), and in human B cells after infection by hepatitis C virus. To understand how viruses signal AID induction in the host we asked whether the AID response was abrogated in cells deficient in the interferon pathway or in signaling via the Toll-like receptors. Here we show that AID is not an interferon responsive gene and abrogation of Toll-like receptor signaling does not diminish the AID response. However, we found that NF-kappaB was required for expression of virally induced AID. Since NF-kappaB binds and activates the AID promoter, these results mechanistically link viral infection with AID transcription. Thus, induction of AID by viruses could be the result of several signaling pathways that culminate in NF-kappaB activation, underscoring the versatility of this host defense program.

Show MeSH
Related in: MedlinePlus