Evolutionary analysis of the anti-viral STAT2 gene of primates and rodents: Signature of different stages of an arms race

Landau, Luane Jandira Bueno; Fam, Bibiana Sampaio de Oliveira; Yépez, Yuri; Caldas-Garcia, Gabriela Barreto; Pissinatti, Alcides; Falótico, Tiago; Reales, Guillermo; Schüler‐Faccini, Lavínia; Sortica, Vinicius Albuquerque; Bortolini, María Cátira

doi:10.1016/j.meegid.2021.105030

Cited by 2 publications

(3 citation statements)

References 136 publications

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“…Although single amino acid changes can disrupt NS5 binding, these also affect IRF9 binding 11 and thus likely are deleterious. Furthermore, it appears that resistance determinants must be acquired in a specific order that maintains STAT2 stability and signaling function, which is consistent with previous work indicating that coevolution of some STAT2 residues likely resulted from impacts to STAT2 functionality 9 . The need for multiple changes in a specific order illustrates the concept of an evolutionary ridge where there is narrow path between two phenotypes (susceptibility and resistance) that must be followed to maintain functionality 16 .…”

Section: Discussionsupporting

confidence: 88%

“…Previous studies reported that STAT2 in some mammalian lineages, such as primates and rodents, has evolved under positive selection 9 , suggesting that it has engaged in one or more host-pathogen genetic conflicts and that STAT2 evolution has impacted the differential susceptibility seen between some primate and rodent species. However, functional studies have not been conducted to assess the precise impact of STAT2 sequence change across mammalian evolution on flavivirus NS5 antagonism.…”

Section: Introductionmentioning

confidence: 99%

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Evolution of STAT2 resistance to flavivirus NS5 occurred multiple times despite genetic constraints

Veit,

Salim,

Jung

et al. 2024

Nat Commun

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Zika and dengue virus nonstructural protein 5 antagonism of STAT2, a critical interferon signaling transcription factor, to suppress the host interferon response is required for viremia and pathogenesis in a vertebrate host. This affects viral species tropism, as mouse STAT2 resistance renders only immunocompromised or humanized STAT2 mice infectable. Here, we explore how STAT2 evolution impacts antagonism. By measuring the susceptibility of 38 diverse STAT2 proteins, we demonstrate that resistance arose numerous times in mammalian evolution. In four species, resistance requires distinct sets of multiple amino acid changes that often individually disrupt STAT2 signaling. This reflects an evolutionary ridge where progressive resistance is balanced by the need to maintain STAT2 function. Furthermore, resistance may come with a fitness cost, as resistance that arose early in lemur evolution was subsequently lost in some lemur lineages. These findings underscore that while it is possible to evolve resistance to antagonism, complex evolutionary trajectories are required to avoid detrimental host fitness consequences.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Evolution of STAT2 resistance to flavivirus NS5 occurred multiple times despite genetic constraints

Veit,

Salim,

Jung

et al. 2024

Nat Commun

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“…An amazingly multitasking protein [ 66 , 67 ], NS5 of flaviviruses also suppresses cellular IFN response [ 68 ]. A subset of NS5 ( Table 1 ) promotes proteasomal degradation of STAT2, as shown in detail for the DENV and ZIKV orthologs [ 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]. Interestingly, NS5 of both viruses were found to exhibit STAT2 species specificity, i.e., they degraded human STAT2 (hSTAT2), but not mouse STAT2 (mSTAT2), as elaborated later.…”

Section: Stat2 Degradation By the Ubiquitin–proteasome System (Ups)mentioning

confidence: 99%

Mechanisms of Viral Degradation of Cellular Signal Transducer and Activator of Transcription 2

Barik¹

2022

IJMS

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Virus infection of eukaryotes triggers cellular innate immune response, a major arm of which is the type I interferon (IFN) family of cytokines. Binding of IFN to cell surface receptors triggers a signaling cascade in which the signal transducer and activator of transcription 2 (STAT2) plays a key role, ultimately leading to an antiviral state of the cell. In retaliation, many viruses counteract the immune response, often by the destruction and/or inactivation of STAT2, promoted by specific viral proteins that do not possess protease activities of their own. This review offers a summary of viral mechanisms of STAT2 subversion with emphasis on degradation. Some viruses also destroy STAT1, another major member of the STAT family, but most viruses are selective in targeting either STAT2 or STAT1. Interestingly, degradation of STAT2 by a few viruses requires the presence of both STAT proteins. Available evidence suggests a mechanism in which multiple sites and domains of STAT2 are required for engagement and degradation by a multi-subunit degradative complex, comprising viral and cellular proteins, including the ubiquitin–proteasomal system. However, the exact molecular nature of this complex and the alternative degradation mechanisms remain largely unknown, as critically presented here with prospective directions of future study.

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Evolutionary analysis of the anti-viral STAT2 gene of primates and rodents: Signature of different stages of an arms race

Cited by 2 publications

References 136 publications

Evolution of STAT2 resistance to flavivirus NS5 occurred multiple times despite genetic constraints

Evolution of STAT2 resistance to flavivirus NS5 occurred multiple times despite genetic constraints

Mechanisms of Viral Degradation of Cellular Signal Transducer and Activator of Transcription 2

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