SurveySilencing STATs: lessons from paramyxovirus interferon evasion
Introduction
Cytokines and growth factors control diverse cellular processes from embryonic development to immune regulation, and binding of these signaling proteins to their specific transmembrane receptors activates intracellular signal transduction systems that initiate the signal-specific phenotypic changes. Signal transducer and activator of transcription (STAT) family proteins are critical to the action of most cytokines and growth factors, as they directly regulate cellular gene expression [1]. STAT signaling pathways normally function to precisely regulate cellular and organismal physiology, but defective or hyperactive STAT signaling has been associated with several human diseases such as chronic inflammation and cancer [2]. Due to their essential roles in immediate signaling events, it has been postulated that STAT transcription factors represent ideal targets for rational therapeutic intervention for these diseases [3]. The value of STAT-directed interference with cytokine signaling is well supported by the actions of some enveloped RNA viruses that have evolved STAT targeting as a means to escape the host immune response controlled by interferon (IFN). Recent investigations have revealed that paramyxoviruses encode IFN evasion molecules that are efficient STAT antagonists. While the viral strategies are phenotypically similar in targeting and inhibiting STAT protein functions, the molecular details of STAT-directed immune suppression are as diverse as the viruses themselves. Despite the idiosyncrasies of individual cytokine signaling events, the high degree of homology among the mammalian STAT pathways predicts that lessons learned from viral evasion of the IFN system will be instructive for identifying mechanisms of STAT inhibition that could be applied therapeutically.
Section snippets
Paramyxovirus V proteins are STAT-targeting IFN inhibitors
Paramyxoviruses encompass a large family of enveloped, negative strand RNA viruses that cause myriad zoonotic diseases including significant human pathogens like measles virus, mumps virus, and Nipah virus. The large family Paramyxoviridae is subdivided into several genera, including the Rubulavirus, Henipavirus, and Morbillivirus groups (reviewed in [4]). All of these viruses share common genetic features including a polycistronic gene that encodes two or more viral proteins from overlapping
Rubulaviruses assemble STAT-targeting ubiquitin ligase enzymes
The dynamic control of STAT protein activity in uninfected cells is regulated primarily at the level of nuclear–cytoplasmic distribution. STATs are activated by receptor-induced tyrosine phosphorylation, dimerize via intermolecular SH2-phosphotyrosine interactions, and accumulate in the nucleus where they bind to target gene promoters. The STAT dimers are inactivated in the nucleus by tyrosine phosphatase-mediated dephosphorylation rather than by changes in protein stability [13], [14], [15].
Henipaviruses sequester STATs in high molecular weight complexes
Nipah virus and Hendra virus are the two known species of a recently-emerged deadly paramyxovirus genus, Henipavirus, that was responsible for outbreaks of zoonotic respiratory disease and fatal encephalitis in humans and livestock in Malaysia and Australia [68], [69]. Both Henipavirus species share V-dependent IFN signaling evasion properties with other paramyxoviruses [45], [70], [71], [72], but unlike the Rubulavirus V proteins do not induce STAT destabilization.
Nucleotide sequencing of the
Conclusions
The diverse mechanisms that have evolved for V protein-dependent IFN evasion provide many insights into STAT protein inhibition that could not be easily discerned by laboratory investigations and are relevant to the analysis of virus–host interaction, vaccine production, and cytokine biology. Discovery of new paramyxoviruses and their IFN evasion properties will almost certainly reveal novel mechanisms of STAT protein-directed or other means of IFN antagonism, and may also uncover new functions
Acknowledgements
The help and support of all current and former members of the Horvath Laboratory is gratefully acknowledged, as is the continued advice and friendship of many mentors, collaborators and colleagues who have supported our work in STAT biology and paramyxovirology. Research in the Horvath Laboratory is sponsored by the National Institutes of Health and the American Cancer Society.
References (87)
- et al.
Two mRNAs that differ by two nontemplated nucleotides encode the amino coterminal proteins P and V of the paramyxovirus SV5
Cell
(1988) - et al.
The paramyxovirus SV5 V protein binds two atoms of zinc and is a structural component of virions
Virology
(1995) - et al.
Measles virus V protein binds zinc
Virology
(1994) - et al.
Recovery of paramyxovirus simian virus 5 with a V protein lacking the conserved cysteine-rich domain: the multifunctional V protein blocks both interferon-beta induction and interferon signaling
Virology
(2002) - et al.
The V proteins of simian virus 5 and other paramyxoviruses inhibit induction of interferon-beta
Virology
(2002) - et al.
Regulation of interferon-alpha responsiveness by the duration of Janus kinase activity
J. Biol. Chem.
(1997) - et al.
The V protein of human parainfluenza virus 2 antagonizes type I interferon responses by destabilizing signal transducer and activator of transcription 2
Virology
(2001) - et al.
C terminal Cys-rich region of mumps virus structural V protein correlates with block of interferon alpha and gamma signal transduction pathway through decrease of STAT 1-alpha
Biochem. Biophys. Res. Commun.
(2001) - et al.
Paramyxoviridae use distinct virus-specific mechanisms to circumvent the interferon response
Virology
(2000) - et al.
Paramyxoviruses SV5 and HPIV2 assemble STAT protein ubiquitin ligase complexes from cellular components
Virology
(2002)
The carboxyl segment of the mumps virus V protein associates with Stat proteins in vitro via a tryptophan-rich motif
Virology
Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA
Cell
STAT proteins and transcriptional responses to extracellular signals
TIBS
The V protein of the paramyxovirus SV5 interacts with damage-specific DNA binding protein
Virology
Cullin 4A associates with the UV-damaged DNA-binding protein DDB
J. Biol. Chem.
Stat protein transactivation domains recruit p300/CBP through widely divergent sequences
J. Biol. Chem.
STAT3 activation by type I interferons is dependent on specific tyrosines located in the cytoplasmic domain of interferon receptor chain 2c. Activation of multiple STATs proceeds through the redundant usage of two tyrosine residues
J. Biol. Chem.
Direct association of STAT3 with the IFNAR-1 chain of the human type I interferon receptor
J. Biol. Chem.
Catalytically active TYK2 is essential for interferon-beta-mediated phosphorylation of STAT3 and interferon-alpha receptor-1 (IFNAR-1) but not for activation of phosphoinositol 3-kinase
J. Biol. Chem.
Suicide process of renal cell carcinoma cells encountering mumps virus
FEBS Lett.
Interleukin-6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas
FEBS Lett.
Nipah virus—a potential agent of bioterrorism?
Antiviral Res.
Nipah virus: a recently emergent deadly paramyxovirus
Science
Molecular biology of Hendra and Nipah viruses
Microbes Infect.
Measles virus suppresses interferon-alpha signaling pathway: suppression of Jak1 phosphorylation and association of viral accessory proteins, C and V, with interferon-alpha receptor complex
Virology
Measles virus activates NF-kappa B and STAT transcription factors and production of IFN-alpha/beta and IL-6 in the human lung epithelial cell line A549
Virology
NP:P and NP:V interactions of the paramyxovirus simian virus 5 examined using a novel protein:protein capture assay
Virology
Cytoplasmic inclusions of respiratory syncytial virus-infected cells: formation of inclusion bodies in transfected cells that coexpress the nucleoprotein, the phosphoprotein, and the 22K protein
Virology
Localization and characterization of Sendai virus nonstructural C and C′ proteins by antibodies against synthetic peptides
Virus Res.
A road map for those who don’t know JAK–STAT
Science
Series introduction. JAK–STAT signaling in human disease
J. Clin. Invest.
Transcription factors as targets for cancer therapy
Nat. Rev. Cancer
The V protein of simian virus 5 inhibits interferon signalling by targeting STAT1 for proteasome-mediated degradation
J. Virol.
Naturally occurring substitutions in the P/V gene convert the noncytopathic paramyxovirus simian virus 5 into a virus that induces alpha/beta interferon synthesis and cell death
J. Virol.
The paramyxovirus simian virus 5 V protein slows progression of the cell cycle
J. Virol.
Identification of a nuclear Stat1 protein tyrosine phosphatase
Mol. Cell. Biol.
A nuclear protein tyrosine phosphatase is required for the inactivation of Stat1
Proc. Natl. Acad. Sci. U.S.A.
The rapid inactivation of nuclear tyrosine phosphorylated Stat1 depends on a protein tyrosine phosphatase
EMBO J.
STAT2 acts as a host range determinant for species-specific paramyxovirus interferon antagonism and simian virus 5 replication
J. Virol.
Selective STAT protein degradation induced by paramyxoviruses requires both STAT1 and STAT2, but is independent of alpha/beta interferon signal transduction
J. Virol.
Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures
J. Gen. Virol.
C-terminal region of STAT-1alpha is not necessary for its ubiquitination and degradation caused by mumps virus V protein
J. Virol.
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