Silencing STATs: lessons from paramyxovirus interferon evasion

doi:10.1016/j.cytogfr.2004.02.003

Cytokine & Growth Factor Reviews

Volume 15, Issues 2–3, April–June 2004, Pages 117-127

https://doi.org/10.1016/j.cytogfr.2004.02.003 Get rights and content

Abstract

The signal transducer and activator of transcription (STAT) family proteins are essential mediators of cytokine and growth factor functions. The interferon (IFN) family of cytokines is well known as modulators of both innate and adaptive anti-microbial immunity. In response to the evolutionary struggle between host and pathogen, many viruses have developed strategies to bypass the IFN antiviral system. Uniquely, the paramyxoviruses have developed the ability to efficiently inactivate STAT protein function, in many cases using a single virus-encoded protein called ‘V’. The V protein plays a central role in STAT inhibition, but mechanistic studies have revealed great diversity in V-dependent STAT signaling evasion among paramyxovirus species. These examples of IFN evasion by STAT protein inactivation can help define targets for antiviral drug design or improving vaccine regimens. Moreover, understanding these STAT inhibition mechanisms are likely to reveal strategic options for the design of STAT-directed therapeutics for treatment of diseases characterized by cytokine hyperactivity.

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.

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SurveySilencing STATs: lessons from paramyxovirus interferon evasion

Abstract

Introduction

Section snippets

Paramyxovirus V proteins are STAT-targeting IFN inhibitors

Rubulaviruses assemble STAT-targeting ubiquitin ligase enzymes

Henipaviruses sequester STATs in high molecular weight complexes

Conclusions

Acknowledgements

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Survey
Silencing STATs: lessons from paramyxovirus interferon evasion