Mammalian orthoreovirus capsid protein σ3 antagonizes RLR-mediated antiviral responses by degrading MAVS

Dianyu Li; Rongqian Mo; Xiaoyi Li; Rongrong Cheng; Jingying Xie; Hongshan Li; Yanmei Yang; Shasha Li; Huixia Li; Zhenfang Yan; Suocheng Wei; Adi Idris; Xiangrong Li; Ruofei Feng

doi:10.1128/msphere.00236-24

Mammalian orthoreovirus capsid protein σ3 antagonizes RLR-mediated antiviral responses by degrading MAVS

mSphere. 2024 May 17:e0023624. doi: 10.1128/msphere.00236-24. Online ahead of print.

Authors

Dianyu Li^{1

2

3}, Rongqian Mo^{1

2

3}, Xiaoyi Li^{1

2

3}, Rongrong Cheng^{1

2

3}, Jingying Xie^{1

2

3}, Hongshan Li^{1

2

3}, Yanmei Yang^{1

2

3}, Shasha Li^{1

2

3}, Huixia Li^{1

2

4}, Zhenfang Yan^{1

2

3}, Suocheng Wei³, Adi Idris⁵, Xiangrong Li^{1

2

4}, Ruofei Feng^{1

2

4}

Affiliations

¹ Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China.
² Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University, Lanzhou, China.
³ College of Life science and Engineering, Northwest Minzu University, Lanzhou, China.
⁴ Engineering Research Center of Key Technology and Industrialization of Cell-based Vaccine, Ministry of Education, Biomedical Research Center, Northwest Minzu University, Lanzhou, China.
⁵ Centre for Immunology and Infection Control, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, Queensland, Australia.

PMID: 38757961
DOI: 10.1128/msphere.00236-24

Abstract

Mammalian orthoreovirus (MRV) outer capsid protein σ3 is a multifunctional protein containing a double-stranded RNA-binding domain, which facilitates viral entry and assembly. We reasoned that σ3 has an innate immune evasion function. Here, we show that σ3 protein localizes in the mitochondria and interacts with mitochondrial antiviral signaling protein (MAVS) to activate the intrinsic mitochondria-mediated apoptotic pathway. Consequently, σ3 protein promotes the degradation of MAVS through the intrinsic caspase-9/caspase-3 apoptotic pathway. Moreover, σ3 protein can also inhibit the expression of the components of the RNA-sensing retinoic acid-inducible gene (RIG)-like receptor (RLR) signaling pathway to block antiviral type I interferon responses. Mechanistically, σ3 inhibits RIG-I and melanoma differentiation-associated gene 5 expression is independent of its inhibitory effect on MAVS. Overall, we demonstrate that the MRV σ3 protein plays a vital role in negatively regulating the RLR signaling pathway to inhibit antiviral responses. This enables MRV to evade host defenses to facilitate its own replication providing a target for the development of effective antiviral drugs against MRV.

Importance: Mammalian orthoreovirus (MRV) is an important zoonotic pathogen, but the regulatory role of its viral proteins in retinoic acid-inducible gene-like receptor (RLR)-mediated antiviral responses is still poorly understood. Herein, we show that MRV σ3 protein co-localizes with mitochondrial antiviral signaling protein (MAVS) in the mitochondria and promotes the mitochondria-mediated intrinsic apoptotic pathway to cleave and consequently degrade MAVS. Furthermore, tryptophan at position 133 of σ3 protein plays a key role in the degradation of MAVS. Importantly, we show that MRV outer capsid protein σ3 is a key factor in antagonizing RLR-mediated antiviral responses, providing evidence to better unravel the infection and transmission mechanisms of MRV.

Keywords: RIG-I-like receptor signaling; mammalian orthoreovirus; mitochondrial antiviral signaling protein; σ3 protein.