scholarly journals Role of Cyclophilin B in Activation of Interferon Regulatory Factor-3

2005 ◽  
Vol 280 (18) ◽  
pp. 18355-18360 ◽  
Author(s):  
Yoko Obata ◽  
Kazuo Yamamoto ◽  
Masanobu Miyazaki ◽  
Kunitada Shimotohno ◽  
Shigeru Kohno ◽  
...  
2008 ◽  
Vol 83 (2) ◽  
pp. 817-829 ◽  
Author(s):  
Nicolas Ruggli ◽  
Artur Summerfield ◽  
Ana R. Fiebach ◽  
Laurence Guzylack-Piriou ◽  
Oliver Bauhofer ◽  
...  

ABSTRACT Pestiviruses prevent alpha/beta interferon (IFN-α/β) production by promoting proteasomal degradation of interferon regulatory factor 3 (IRF3) by means of the viral Npro nonstructural protein. Npro is also an autoprotease, and its amino-terminal coding sequence is involved in translation initiation. We previously showed with classical swine fever virus (CSFV) that deletion of the entire Npro gene resulted in attenuation in pigs. In order to elaborate on the role of the Npro-mediated IRF3 degradation in classical swine fever pathogenesis, we searched for minimal amino acid substitutions in Npro that would specifically abrogate this function. Our mutational analyses showed that degradation of IRF3 and autoprotease activity are two independent but structurally overlapping functions of Npro. We describe two mutations in Npro that eliminate Npro-mediated IRF3 degradation without affecting the autoprotease activity. We also show that the conserved standard sequence at these particular positions is essential for Npro to interact with IRF3. Surprisingly, when these two mutations are introduced independently in the backbones of highly and moderately virulent CSFV, the resulting viruses are not attenuated, or are only partially attenuated, in 8- to 10-week-old pigs. This contrasts with the fact that these mutant viruses have lost the capacity to degrade IRF3 and to prevent IFN-α/β induction in porcine cell lines and monocyte-derived dendritic cells. Taken together, these results demonstrate that contrary to previous assumptions and to the case for other viral systems, impairment of IRF3-dependent IFN-α/β induction is not a prerequisite for CSFV virulence.


2012 ◽  
Vol 86 (9) ◽  
pp. 4947-4955 ◽  
Author(s):  
D. Ishibashi ◽  
R. Atarashi ◽  
T. Fuse ◽  
T. Nakagaki ◽  
N. Yamaguchi ◽  
...  

2012 ◽  
Vol 87 (1) ◽  
pp. 16-24 ◽  
Author(s):  
S. Chattopadhyay ◽  
V. Fensterl ◽  
Y. Zhang ◽  
M. Veleeparambil ◽  
M. Yamashita ◽  
...  

Cytokine ◽  
2008 ◽  
Vol 43 (3) ◽  
pp. 259
Author(s):  
Kenrie P. Hui ◽  
Suki M. Lee ◽  
Chung-yan Cheung ◽  
Iris H.Y. Ng ◽  
Leo L.M. Poon ◽  
...  

2021 ◽  
Vol 95 (9) ◽  
Author(s):  
K. E. Johnson ◽  
P. A. Sylvester ◽  
C. N. Jondle ◽  
C. A. Aurubin ◽  
V. L. Tarakanova

ABSTRACT Gammaherpesviruses are ubiquitous pathogens that establish lifelong infections and are associated with several malignancies, including B cell lymphomas. Uniquely, these viruses manipulate B cell differentiation to establish long-term latency in memory B cells. This study focuses on the interaction between gammaherpesviruses and interferon regulatory factor 3 (IRF-3), a ubiquitously expressed transcription factor with multiple direct target genes, including beta interferon (IFN-β), a type I IFN. IRF-3 attenuates acute replication of a plethora of viruses, including gammaherpesvirus. Furthermore, IRF-3-driven IFN-β expression is antagonized by the conserved gammaherpesvirus protein kinase during lytic virus replication in vitro. In this study, we have uncovered an unexpected proviral role of IRF-3 during chronic gammaherpesvirus infection. In contrast to the antiviral activity of IRF-3 during acute infection, IRF-3 facilitated establishment of latent gammaherpesvirus infection in B cells, particularly, germinal center and activated B cells, the cell types critical for both natural infection and viral lymphomagenesis. This proviral role of IRF-3 was further modified by the route of infection and viral dose. Furthermore, using a combination of viral and host genetics, we show that IRF-3 deficiency does not rescue attenuated chronic infection of a protein kinase null gammaherpesvirus mutant, highlighting the multifunctional nature of the conserved gammaherpesvirus protein kinases in vivo. In summary, this study unveils an unexpected proviral nature of the classical innate immune factor, IRF-3, during chronic virus infection. IMPORTANCE Interferon regulatory factor 3 (IRF-3) is a critical component of the innate immune response, in part due to its transactivation of beta interferon (IFN-β) expression. Similar to that observed in all acute virus infections examined to date, IRF-3 suppresses lytic viral replication during acute gammaherpesvirus infection. Because gammaherpesviruses establish lifelong infection, this study aimed to define the antiviral activity of IRF-3 during chronic infection. Surprisingly, we found that, in contrast to acute infection, IRF-3 supported the establishment of gammaherpesvirus latency in splenic B cells, revealing an unexpected proviral nature of this classical innate immune host factor.


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