LncRNA NEAT1 Potentiates SREBP2 Activity to Promote Inflammatory Macrophage Activation and Limit Hantaan Virus Propagation

Yongheng Yang; Mengyun Li; Yongtao Ma; Wei Ye; Yue Si; Xuyang Zheng; He Liu; Linfeng Cheng; Liang Zhang; Hui Zhang; Xijing Zhang; Yingfeng Lei; Lixin Shen; Fanglin Zhang; Hongwei Ma

doi:10.3389/fmicb.2022.849020

LncRNA NEAT1 Potentiates SREBP2 Activity to Promote Inflammatory Macrophage Activation and Limit Hantaan Virus Propagation

Front Microbiol. 2022 Apr 13:13:849020. doi: 10.3389/fmicb.2022.849020. eCollection 2022.

Authors

Yongheng Yang^{1

2}, Mengyun Li^{1

2}, Yongtao Ma³, Wei Ye², Yue Si², Xuyang Zheng^{2

4}, He Liu², Linfeng Cheng², Liang Zhang², Hui Zhang², Xijing Zhang⁵, Yingfeng Lei², Lixin Shen¹, Fanglin Zhang², Hongwei Ma^{2

5}

Affiliations

¹ College of Life Sciences, Northwest University, Xi'an, China.
² Department of Microbiology, School of Basic Medicine, The Fourth Military Medical University, Xi'an, China.
³ Department of Emergency, Children's Hospital of Kaifeng City, Kaifeng, China.
⁴ Department of Infectious Diseases, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
⁵ Department of Anesthesiology and Critical Care Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.

Abstract

As the global prototypical zoonotic hantavirus, Hantaan virus (HTNV) is prevalent in Asia and is the leading causative agent of severe hemorrhagic fever with renal syndrome (HFRS), which has profound morbidity and mortality. Macrophages are crucial components of the host innate immune system and serve as the first line of defense against HTNV infection. Previous studies indicated that the viral replication efficiency in macrophages determines hantavirus pathogenicity, but it remains unknown which factor manipulates the macrophage activation pattern and the virus-host interaction process. Here, we performed the transcriptomic analysis of HTNV-infected mouse bone marrow-derived macrophages and identified the long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1), especially the isoform NEAT1-2, as one of the lncRNAs that is differentially expressed at the early phase. Based on coculture experiments, we revealed that silencing NEAT1-2 hinders inflammatory macrophage activation and facilitates HTNV propagation, while enhancing NEAT1-2 transcription effectively restrains viral replication. Furthermore, sterol response element binding factor-2 (SREBP2), which controls the cholesterol metabolism process, was found to stimulate macrophages by promoting the production of multiple inflammatory cytokines upon HTNV infection. NEAT1-2 could potentiate SREBP2 activity by upregulating Srebf1 expression and interacting with SREBP2, thus stimulating inflammatory macrophages and limiting HTNV propagation. More importantly, we demonstrated that the NEAT1-2 expression level in patient monocytes was negatively correlated with viral load and HFRS disease progression. Our results identified a function and mechanism of action for the lncRNA NEAT1 in heightening SREBP2-mediated macrophage activation to restrain hantaviral propagation and revealed the association of NEAT1 with HFRS severity.

Keywords: HFRS; Hantaan virus; NEAT1; SREBP2; hantavirus; inflammatory macrophage; lncRNA.