Paramyxovirus disruption of interferon signal transduction: STATus report - PubMed (original) (raw)

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Paramyxovirus disruption of interferon signal transduction: STATus report

Aparna Ramachandran et al. J Interferon Cytokine Res. 2009 Sep.

Abstract

RNA viruses in the paramyxovirus family have evolved a number of strategies to escape host cell surveillance and antiviral responses. One mechanism exploited by a number of viruses in this family is direct targeting of cytokine-inducible transcription regulators in the STAT family. Diverse members of this large virus family effectively suppress STAT signaling by the actions of their V proteins, or the related proteins derived from alternate viral mRNAs. These viral proteins have distinct means of targeting STATs, resulting in a variety of negative effects on STATs and their signal transduction. Recent developments in understanding STAT targeting will be reviewed.

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Figures

FIG. 1.

FIG. 1.

Distinct mechanism of STAT inhibition by different paramyxoviruses. (A) Sequence alignment of the highly conserved C-terminal domain (CTD) from various paramyxovirus V proteins mentioned in text. Histidine and 7 cysteine residues and zinc fingers 1 and 2 are indicated. (B) Schematic diagram of PIV5, measles, and Nipah V proteins drawn to scale showing the key features, including the CTD (pink box) and important regions and residues for STAT interaction. (Top) PIV5 V protein. A single region for STAT interaction has not been described, but residue N100 in the N-terminal domain shared between P and V has been shown to provide species-specific interaction with human STAT2. (Middle) Measles V protein. The measles V CTD has a unique extension (green) of unknown significance. The CTD alone is necessary and sufficient for STAT2 interaction. Within the CTD D248 has been found to be important in measles V protein STAT2 interaction. The STAT1 interaction in measles V protein is mediated by residues 110–130 (red box) that includes tyrosine 110 (Y110). (Bottom) Nipah V protein. The Henipavirus CTD is dispensable for STAT interaction. Residues 100–160 (red box) are necessary and sufficient for STAT1 binding, whereas STAT2 association requires STAT1 and a larger region involving residues 100–300. The STAT1-binding domain is also an interaction site for Polo-like kinase 1 (PLK1).

FIG. 2.

FIG. 2.

Structural representations of paramyxovirus V proteins. (A) The PIV5 V-dependent degradation complex (VDC) complex (PDB accession no. 2B5L) crystal structure (Li and others 2006). The PIV5 V protein (in red) associates with the β-propeller cluster of DDB1 (in green), which is associated with Cullin 4A (in pink) and Roc 1 (in yellow). The crystal structure of PIV5 in complex with DDB1 shows that both the N-terminal domains (NTDs) and C-terminal domains (CTDs) are required to mediate interaction with the components of E3 ligase machinery. The PIV5 V protein is positioned at the substrate-binding cleft of the E3 complex. (B) Structural model of measles V protein CTD showing the surface residues unique to measles V protein that were demonstrated to be important for mediating interaction with STAT2. The measles virus V protein sequence was modeled on the SV5 structure (PDB accession no. 2B5L) by use of the Swiss PDB viewer. Coloration corresponds to the activity level of mutations for each position (Ramachandran and others 2008). Gray represents nonmutated residues, cyan indicates neutral substitutions, yellow represents mutations that retain 30% to 80% activity, and red represents mutations that are >70% defective (F246 and D248) (Ramachandran and others 2008).

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