Vaccinia Virus B1R Kinase Interacts with JIP1 and Modulates c-Jun-Dependent Signaling

Abstract

Viruses have to adjust to the host cell to guarantee their life cycle and survival. This aspect of the virus-host cell interaction is probably performed by viral proteins, such as serine-threonine kinases, that are present early during infection. Vaccinia virus has an early Ser-Thr kinase, B1R, which, although required for successful viral infection, is poorly characterized regarding its effects on cellular proteins, and thus, its potential contribution to pathogenesis is not known. Signaling by mitogen-activated protein kinase (MAPK) is mediated by the assembly of complexes between these kinases and the JIP scaffold proteins. To understand how vaccinia virus B1R can affect the host, its roles in the cellular signaling by MAPK complexes and c-Jun activation have been studied. Independently of its kinase activity, B1R can interact with the central region of the JIP1 scaffold protein. The B1R-JIP1 complex increases the amount of MAPK bound to JIP1; thus, MKK7 and TAK1 either bind with higher affinity or bind more stably to JIP1, while there is an increase in the phosphorylation state of JNK bound to JIP1. The functional consequence of these more stable interactions is an increase in the activity of transcription factors, such as c-Jun, that respond to these complexes. Furthermore, B1R is also able to directly phosphorylate c-Jun in residues different from those targeted by JNK and, thus, B1R can also cooperate by an independent route in c-Jun activation. Vaccinia virus B1R can thus modulate the signaling of pathways that respond to cellular stress.

Orthopoxvirus targets for the development of new antiviral agents

“…Both H5R and B1R co-localize as punctate sites in the cytoplasm that are precursors to sites of viral DNA synthesis (Domi and Beaud, 2000). Cellular proteins are also phosphorylated by this kinase including p53, which results in the ubiquitination and degradation of p53 (Santos et al, 2004), and other cellular signaling pathways related to cellular stress (Santos et al, 2006). The B1R kinase also inhibits CD1d-mediated antigen presentation and antagonizes an important innate immune response (Webb et al, 2006).…”

Role of cell signaling in poxvirus-mediated foreign gene expression in mammalian cells

“…VV has the ability to bind cells and activate cellular mitogen-activated protein kinases (MAPK) including p38 MAPK [38], JNK [39], and ERK [40, 41], leading to permissive virus replication in a variety of diverse cell lines. Experimental studies using A31 cells (a clone derived from mouse Balb/c 3T3 cells) have demonstrated that VV triggers a sustained activation of MAPK/ERK1/2 and protein kinase A at an early stage of infection and whose activation are required for VV multiplication [41].…”

Small peptide inhibitor of JNKs protects against MPTP-induced nigral dopaminergic injury via inhibiting the JNK-signaling pathway

“…38,45 This proapoptotic protein Bax forms pores in the outer mitochondrial membrane which helps in the releasing of cyt c. 46 As Tat-JBD could inhibit the activation of JNK, we showed that treatment of the peptides inhibited the phosphorylation of Bcl-2 proteins, increased the interaction of Bcl-2 with Bax, prevented Bax translocation to mitochondria, and attenuated the release of cyt c and caspase-3 activation. 14,19,39,42 This suggests that the mitochondriadependent apoptosis pathway mediated by JNKs activation is also involved in dopaminergic neuronal apoptosis induced by MPTP-injury.…”

“…12,13 The JNK-binding domain of JIP-1 (JBD) is located at residues 127-282, the N terminus of the protein. 14 Eilers's 15 results showed overexpression of JBD can inhibit JNK activation and reduce the apoptosis induced by the withdrawal of nerve growth factor in PC12 cells. Apoptosis was also reduced or prevented by overexpression of the JBD in the insulin-secreting cells or sympathetic neurons.…”