Mechanisms of host type I interferon response modulation by the nucleocapsid proteins of alpha- and betacoronaviruses

Abstract

Coronaviruses can have a devastating impact on the health of humans and animals. Porcine epidemic diarrhea virus (PEDV) causes extremely high fatality rates in neonatal piglets, whereas severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic in humans. As a critical component of the host antiviral innate immune response, type I interferon production and signaling play a very important role, especially in the initial phase of the antiviral responses. Coronaviruses have evolved multiple ways to counteract type I interferon responses. Although the primary functions of the nucleocapsid protein are to facilitate viral RNA replication and package viral genomic RNA into virions, recent studies have shown that the nucleocapsid protein is also involved in virus-host interactions. The aim of this review is to summarize our current understanding of how the nucleocapsid proteins of PEDV and SARS-CoV-2 modulate type I interferon responses. This knowledge will be useful for developing strategies to combat coronavirus infections.

Diversity of Short Linear Interaction Motifs in SARS-CoV-2 Nucleocapsid Protein

“…Even though it provides a major antigen, it is not immuno-dominant as the spike protein. Besides its eponymous structural role in viral assembly (Carlson et al, 2022;Masters, 2019;Zhao et al, 2023), N-protein is highly multi-functional with a large host interactome (Gordon et al, 2020;Kruse et al, 2021;Wu et al, 2023;Zheng et al, 2021), including interactions with proteins of the type 1 interferon signaling pathway (Li et al, 2020;Mu et al, 2020;Yelemali et al, 2022), the inflammasome (Pan et al, 2021), complement activation (Gao et al, 2022), lipid metabolism (Yuan et al, 2021), and expression and binding to cytokines (Karwaciak et al, 2021;López-Muñoz et al, 2022). Among interactions described in greatest biophysical detail are the complex formation with G3BP1 leading to rewiring of stress granules (Biswal et al, 2022;Kruse et al, 2021;Yang et al, 2023), binding of 14-3-3 (Eisenreichova and Boura, 2022;Tugaeva et al, 2021Tugaeva et al, , 2023, and the interaction with host kinases leading to extensive phosphorylation particularly in the linker IDR of intracellular N-protein (Carlson et al, 2020;Syed et al, 2023;Yaron et al, 2022).…”

The Nucleocapsid Proteins of SARS-CoV-2 and Its Close Relative Bat Coronavirus RaTG13 Are Capable of Inhibiting PKR- and RNase L-Mediated Antiviral Pathways

“…Coronavirus N is a multifunctional protein ( 29 , 30 ). In addition to its function in packaging the virus genomic RNA into the ribonucleoprotein complex, it plays a role in many aspects of virus replication, such as modulating the cellular environment to facilitate virus replication ( 13 – 15 , 29 , 30 , 34 , 35 ). Using an ectopic-overexpression system, the SARS-CoV-2 N protein has been shown to inhibit PKR phosphorylation and the formation of stress granules (SGs) induced by the synthetic dsRNA poly(I·C) ( 13 , 14 ).…”

The Interaction between SARS-CoV-2 Nucleocapsid Protein and UBC9 Inhibits MAVS Ubiquitination by Enhancing Its SUMOylation

“…This is evident from the absence of IFN-β production and reduced IFN-α production and activity, leading to a persistent viral load in the bloodstream and an exacerbated inflammatory response [4]. SARS-CoV-2 has been shown to encode multiple proteins that manipulate or evade the host's antiviral response, enabling successful infection [5][6][7]. The nucleocapsid protein (N), the most conservative protein among human β coronaviruses, including SARS-CoV-2, responsible for COVID-19, has been implicated in interfering with the host's innate immune response.…”