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

Abstract

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.

Structural mechanism of CRL4‐instructed STAT2 degradation via a novel cytomegaloviral DCAF receptor

“…For example, Zika virus (ZIKV; Grant et al , 2016 ), Dengue virus (DENV; Jones et al , 2005 ; Ashour et al , 2009 ), paramyxoviruses (Parisien et al , 2001 , 2002b ), MCMV (Zimmermann et al , 2005 ; Trilling et al , 2011 ) and HCMV (Le‐Trilling et al , 2020 ) induce STAT2 degradation along the ubiquitin–proteasome pathway (UPS). Intriguingly, the responsible virus proteins act as adapters that place STAT2 into the sphere of influence of cellular E3 ubiquitin ligases (E3s; Ulane & Horvath, 2002 ; Le‐Trilling & Trilling, 2020 ; Barik, 2022 ).…”

Investigation of the impact of AXL, TLR3, and STAT2 in congenital Zika syndrome through genetic polymorphisms and protein–protein interaction network analyses

“…In this sense, AXL , TLR3 , and STAT2 genes and their proteins have been widely described as important for these processes (Agrelli et al, 2019; Nelson et al, 2020; Serman & Gack, 2019). The role of these proteins in viral recognition and antiviral response, in addition to ZIKV, has been described for several other viruses, including flaviviruses (both AXL, TLR3, and STAT2 proteins), filoviruses (e.g., ebolavirus) (AXL), SARS‐CoV‐2 (both TLR3 and STAT2), neuroinvasive viruses (e.g., herpes virus, arbovirus, enterovirus, human immunodeficiency virus, among others) (TLR3), cytomegalovirus (STAT2), among others (Barik, 2022; Miorin et al, 2020; Nazmi et al, 2014; Pati et al, 2021; Suh et al, 2009; Verma & Bharti, 2017; Wang et al, 2021). So far, very few studies have investigated the role of common genetic variants on the susceptibility to congenital anomalies induced by ZIKV.…”

Genomics: Infectious Disease and Host–Pathogen Interaction

“…Genomics and transcriptomic analysis are involved in the investigation of infectious diseases and host–pathogen interactions as well. While innate immune responses such as type I interferon (IFN) family cytokines can be stimulated by viral infections, Barik S. reviewed the mechanisms whereby IFN further triggers a STAT2 signaling cascade leading to an antiviral state of the cell [ 7 ]. On the other hand, the mapping of small RNA reads from Huh7 cells infected with Ebola virus to the Ebola genome revealed the presence of two novel Ebola-virus-derived microRNAs which may target host genes [ 13 ].…”

“…This Special Issue of the International Journal of Molecular Sciences entitled “Genomics: Infectious Disease and Host –Pathogen Interaction” contains twelve original articles and three reviews that provide new insights into infectious diseases with regard to biofilm formation [ 1 , 2 , 3 ], diagnostics [ 4 ], vaccine development [ 5 ], and host–pathogen interaction [ 6 , 7 ]; these insights are based on genomic [ 8 , 9 , 10 , 11 , 12 ], transcriptomic [ 13 , 14 ], and microbiomic [ 15 ] studies.…”