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siRNA Electroporation to Modulate Autophagy in Herpes Simplex Virus Type 1-Infected Monocyte-Derived Dendritic Cells

siRNA Electroporation to Modulate Autophagy in Herpes Simplex Virus Type 1-Infected Monocyte-Derived Dendritic Cells

Published on: October 28, 2019

Human Respiratory Syncytial Virus NS2 Protein Induces Autophagy by Modulating Beclin1 Protein Stabilization and

Kim Chiok¹, Swechha M Pokharel¹, Indira Mohanty¹

¹Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State Universitygrid.30064.31, Pullman, Washington, USA.

|January 18, 2022

Abstract:

Paramyxoviruses such as respiratory syncytial virus (RSV) are the leading cause of pneumonia in infants, the elderly, and immunocompromised individuals. Understanding host-virus interactions is essential for the development of effective interventions. RSV induces autophagy to modulate the immune response. The viral factors and mechanisms underlying RSV-induced autophagy are unknown. Here, we identify the RSV nonstructural protein NS2 as the virus component mediating RSV-induced autophagy. We show that NS2 interacts and stabilizes the proautophagy mediator Beclin1 by preventing its degradation by the proteasome. NS2 further impairs interferon-stimulated gene 15 (ISG15)-mediated Beclin1 ISGylation and generates a pool of "hypo-ISGylated" active Beclin1 to engage in functional autophagy. Studies with NS2-deficient RSV revealed that NS2 contributes to RSV-mediated autophagy during infection. The present study is the first report to show direct activation of autophagy by a paramyxovirus nonstructural protein. We also report a new viral mechanism for autophagy induction wherein the viral protein NS2 promotes hypo-ISGylation of Beclin1 to ensure availability of active Beclin1 to engage in the autophagy process. IMPORTANCE Understanding host-virus interactions is essential for the development of effective interventions against respiratory syncytial virus (RSV), a paramyxovirus that is a leading cause of viral pneumonia in infants. RSV induces autophagy following infection, although the viral factors involved in this mechanism are unknown. Here, we identify the RSV nonstructural protein 2 (NS2) as the virus component involved in autophagy induction. NS2 promotes autophagy by interaction with and stabilization of the proautophagy mediator Beclin1 and by impairing its ISGylation to overcome autophagy inhibition. To the best of our knowledge, this is the first report of a viral protein regulating the autophagy pathway by modulating ISGylation of autophagy mediators. Our studies highlight a direct role of a paramyxovirus nonstructural protein in activating autophagy by interacting with the autophagy mediator Beclin1. NS2-mediated regulation of the autophagy and ISGylation processes is a novel function of viral nonstructural proteins to control the host response against RSV.

Insights

Respiratory syncytial virus (RSV) nonstructural protein 2 (NS2) activates autophagy by stabilizing Beclin1 and impairing its ISGylation. This study reveals a novel viral mechanism for controlling host immune responses during RSV infection.

Area of Science:

Virology
Cell Biology
Immunology

Background:

Respiratory syncytial virus (RSV) is a major cause of pneumonia in vulnerable populations.
RSV infection triggers autophagy, a cellular process crucial for immune response modulation.
The specific viral factors and mechanisms driving RSV-induced autophagy remain largely unknown.

Purpose of the Study:

To identify the viral component responsible for inducing autophagy during RSV infection.
To elucidate the molecular mechanisms by which RSV manipulates autophagy.
To understand how viral protein activity impacts host-pathogen interactions.

Main Methods:

Investigated the role of RSV nonstructural protein 2 (NS2) in autophagy induction.
Analyzed the interaction between NS2 and the proautophagy mediator Beclin1.
Assessed the impact of NS2 on Beclin1 degradation and ISGylation.
Utilized NS2-deficient RSV to confirm NS2's role during infection.

Main Results:

RSV nonstructural protein 2 (NS2) directly induces autophagy.
NS2 stabilizes Beclin1 by inhibiting its proteasomal degradation.
NS2 impairs interferon-stimulated gene 15 (ISG15)-mediated Beclin1 ISGylation, increasing active Beclin1.
NS2 is essential for efficient RSV-mediated autophagy during infection.

Conclusions:

RSV NS2 protein is a key viral factor that activates autophagy.
NS2 employs a novel mechanism involving Beclin1 stabilization and hypo-ISGylation to promote autophagy.
This viral strategy helps RSV evade host immune defenses.

Read full analysis

Keywords:

autophagy paramyxovirus respiratory syncytial virus

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