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Nonstructural protein 1 widespread RNA decay phenotype varies among coronaviruses.

ABSTRACT: Extensive remodeling of host gene expression by nonstructural protein 1 (nsp1) of coronaviruses is a well-documented and conserved aspect of coronavirus-host takeover. Using comparative transcriptomics we investigated the diversity of transcriptional targets between various nsp1 proteins. Additionally, affinity purification followed by mass spectrometry was implemented to identify common interactors between the different nsp1 proteins. Although we detected widespread RNA destabilization, closely related nsp1 showed little similarities in clustering of targeted genes. We observed a partial overlap in transcriptional targeting between α-CoV 229E and MERS nsp1, which may suggest a common targeting mechanism, as MERS nsp1 preferentially targets nuclear transcripts. Our interactome data show great variability between nsp1 interactions, with 229E nsp1, the smallest nsp1 tested here, interacting with the most number of host proteins. Although nsp1 is a rather well-conserved protein with conserved functions across different coronaviruses, our data indicate that its precise effects on the host cell are virus specific.

SUBMITTER: Bermudez Y

PROVIDER: S-EPMC9794394 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Nonstructural protein 1 widespread RNA decay phenotype varies among coronaviruses.

Bermudez Yahaira Y Miles Jacob J Muller Mandy M

iScience 20221228 1

Extensive remodeling of host gene expression by nonstructural protein 1 (nsp1) of coronaviruses is a well-documented and conserved aspect of coronavirus-host takeover. Using comparative transcriptomics we investigated the diversity of transcriptional targets between various nsp1 proteins. Additionally, affinity purification followed by mass spectrometry was implemented to identify common interactors between the different nsp1 proteins. Although we detected widespread RNA destabilization, closely ...[more]

PMID: 36590901

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Project description:Recent outbreaks caused by coronaviruses and their supposed potential fecal-oral transmission highlight the need for understanding the survival of infectious coronavirus in domestic sewers. To date, the survivability and decay of coronaviruses were predominately studied using small volumes of wastewater (normally 5-30 mL) in vials (in-vial tests). However, real sewers are more complicated than bulk wastewater (wastewater matrix only), in particular the presence of sewer biofilms and different operational conditions. This study investigated the decay of infectious human coronavirus 229E (HCoV-229E) and feline infectious peritonitis virus (FIPV), two typical surrogate coronaviruses, in laboratory-scale reactors mimicking the gravity (GS, gravity-driven sewers) and rising main sewers (RM, pressurized sewers) with and without sewer biofilms. The in-sewer decay of both coronaviruses was greatly enhanced in comparison to those reported in bulk wastewater through in-vial tests. 99% of HCoV-229E and FIPV decayed within 2 h under either GS or RM conditions with biofilms, in contrast to 6-10 h without biofilms. There is limited difference in the decay of HCoV and FIPV in reactors operated as RM or GS, with the T90 and T99 difference of 7-10 min and 14-20 min, respectively. The decay of both coronaviruses in sewer biofilm reactors can be simulated by biphasic first-order kinetic models, with the first-order rate constant 2-4 times higher during the first phase than the second phase. The decay of infectious HCoV and FIPV was significantly faster in the reactors with sewer biofilms than in the reactors without biofilms, suggesting an enhanced decay of these surrogate viruses due to the presence of biofilms and related processes. The mechanism of biofilms in virus adsorption and potential inactivation remains unclear and requires future investigations. The results indicate that the survivability of infectious coronaviruses detected using bulk wastewater overestimated the infectivity risk of coronavirus during wastewater transportations in sewers or the downstream treatment.

Project description:RNA helicases and chaperones are the two major classes of RNA remodeling proteins, which function to remodel RNA structures and/or RNA-protein interactions, and are required for all aspects of RNA metabolism. Although some virus-encoded RNA helicases/chaperones have been predicted or identified, their RNA remodeling activities in vitro and functions in the viral life cycle remain largely elusive. Enteroviruses are a large group of positive-stranded RNA viruses in the Picornaviridae family, which includes numerous important human pathogens. Herein, we report that the nonstructural protein 2CATPase of enterovirus 71 (EV71), which is the major causative pathogen of hand-foot-and-mouth disease and has been regarded as the most important neurotropic enterovirus after poliovirus eradication, functions not only as an RNA helicase that 3'-to-5' unwinds RNA helices in an adenosine triphosphate (ATP)-dependent manner, but also as an RNA chaperone that destabilizes helices bidirectionally and facilitates strand annealing and complex RNA structure formation independently of ATP. We also determined that the helicase activity is based on the EV71 2CATPase middle domain, whereas the C-terminus is indispensable for its RNA chaperoning activity. By promoting RNA template recycling, 2CATPase facilitated EV71 RNA synthesis in vitro; when 2CATPase helicase activity was impaired, EV71 RNA replication and virion production were mostly abolished in cells, indicating that 2CATPase-mediated RNA remodeling plays a critical role in the enteroviral life cycle. Furthermore, the RNA helicase and chaperoning activities of 2CATPase are also conserved in coxsackie A virus 16 (CAV16), another important enterovirus. Altogether, our findings are the first to demonstrate the RNA helicase and chaperoning activities associated with enterovirus 2CATPase, and our study provides both in vitro and cellular evidence for their potential roles during viral RNA replication. These findings increase our understanding of enteroviruses and the two types of RNA remodeling activities.

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Nonstructural protein 1 widespread RNA decay phenotype varies among coronaviruses.

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Nonstructural protein 1 widespread RNA decay phenotype varies among coronaviruses.

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