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Review
. 2008 Jul;20(7):1227-36.
doi: 10.1016/j.cellsig.2007.12.018. Epub 2008 Jan 4.

Modulation of signaling pathways by RNA virus capsid proteins

Matthew D Urbanowski  1 , Carolina S Ilkow, Tom C Hobman
Affiliations
Review

Modulation of signaling pathways by RNA virus capsid proteins

Matthew D Urbanowski et al. Cell Signal. 2008 Jul.

Abstract

Capsid proteins are structural components of virus particles. They are nucleic acid-binding proteins whose main recognized function is to package viral genomes into protective structures called nucleocapsids. Research over the last 10 years indicates that in addition to their role as genome guardians, viral capsid proteins modulate host cell signaling networks. Disruption or alteration of intracellular signaling pathways by viral capsids may benefit replication of the virus by affecting innate immunity and in some cases, may underlie disease progression. In this review, we describe how the capsid proteins from medically relevant RNA viruses interact with host cell signaling pathways.

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Figures

Fig. 1
Fig. 1
Multifunctionality of RNA virus capsid proteins. A generic RNA virus is used as the model. Virions consist of a host-derived lipid envelope containing virus-encoded membrane glycoproteins. The interior of the virion consists of genomic RNA bound to capsid proteins. Upon entry, deposition of nucleocapid into the cytoplasm provides the first opportunity for capsids to interact with signaling proteins. The viral genome is translated to produce structural and nonstructural proteins. The nonstructural proteins function in replication of the genome whereas the structural proteins function in assembly of new virions. Recent evidence suggests that nascent viral capsids also interface with cellular proteins to alter the host cell environment so that it is more permissive for viral replication.
Fig. 2
Fig. 2
Capsid proteins localize to intracellular sites that are not related to virus assembly. West Nile virus (WNV) and Rubella virus (RV) both replicate in the cytoplasm and assemble on membranes of the endoplasmic reticulum and Golgi complex respectively. However, large pools of their capsid proteins localize to the nucleous (WNV) or mitochondria (RV). Cells were infected with WNV (upper panels) or RV (lower panels) and then fixed and processed for indirect immunofluorescence. Nuclei were stained with DAPI and mitochondria were detected with antibodies specific for the matrix protein p32.
Fig. 3
Fig. 3
Flavivirus capsid proteins can affect apoptotic signalling pathways through multiple mechanisms. Numbered blue circles represent points at which capsid proteins act: 1: HCV core protein upregulates activity of transcription factor NF-κB, which leads to increased transcription of pro-survival genes. Core potentiated activation of TNFR may also lead to activation of IκB Kinase (IKK), which in turn phosphorylates and deactivates the NF-κB inhibitor IκB. This allows NF-κB to enhance transcripton of its target genes. 2: HCV core protein binds to the cytoplasmic domain of death receptors leading to potentiation of TNF-α mediated apoptosis, or alternatively, activation of NF-κB, a pathway that requires RIP and IKK. 3: Upregulation of c-FLIP by HCV core results in blocking apoptosis through inhibition of caspase-8 activation. 4: WNV capsid protein promotes p53 mediated apoptosis by blocking interaction of hDM2 with p53, thereby increasing the stability and consequent increase in transcription of pro-apoptotic target genes. 5: HCV core upregulates the levels of ICAD, thus inhibiting caspase mediated DNA cleavage. 6 and 7: The HCV core reportedly upregulates expression anti-apoptotic (Bcl-XL and pro-apoptotic (Bax) Bcl-2 family members that function at the level of mitochondria. 8: HCV core also increases the expression of the pro-apoptotic transcription p53, one of whose functions is to upregulate Bax. For more details, please see text. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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