首页|RIPK3 promotes hantaviral replication by restricting JAK-STAT signaling without triggering necroptosis

RIPK3 promotes hantaviral replication by restricting JAK-STAT signaling without triggering necroptosis

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Hantaan virus(HTNV)is a rodent-borne virus that causes hemorrhagic fever with renal syndrome(HFRS),resulting in a high mortality rate of 15％.Interferons(IFNs)play a critical role in the anti-hantaviral immune response,and IFN pretreatment efficiently restricts HTNV infection by triggering the expression of a series of IFN-stimulated genes(ISGs)through the Janus kinase-signal transducer and activator of transcription 1(JAK-STAT)pathway.However,the tremendous amount of IFNs produced during late infection could not restrain HTNV replication,and the mechanism remains unclear.Here,we demonstrated that receptor-interacting protein kinase 3(RIPK3),a crucial molecule that mediates necroptosis,was activated by HTNV and contributed to hantavirus evasion of IFN responses by inhibiting STAT1 phosphorylation.RNA-seq analysis revealed the upregulation of multiple cell death-related genes after HTNV infection,with RIPK3 identified as a key modulator of viral repli-cation.RIPK3 ablation significantly enhanced ISGs expression and restrained HTNV replication,without affecting the expression of pattern recognition receptors(PRRs)or the production of type Ⅰ IFNs.Conversely,exogenously expressed RIPK3 compromised the host's antiviral response and facilitated HTNV replication.RIPK3-/-mice also maintained a robust ability to clear HTNV with enhanced innate immune responses.Mechanistically,we found that RIPK3 could bind STAT1 and inhibit STAT1 phosphorylation dependent on the protein kinase domain(PKD)of RIPK3 but not its kinase activity.Overall,these observations demonstrated a noncanonical function of RIPK3 during viral infection and have elucidated a novel host innate immunity evasion strategy utilized by HTNV.

Hantaan virus(HTNV)RIPK3InterferonsIFN-stimulated genesSTAT1Innate immune response

Yue Si、Haijun Zhang、Ziqing Zhou、Xudong Zhu、Yongheng Yang、He Liu、Liang Zhang、Linfeng Cheng、Kerong Wang、Wei Ye、Xin Lv、Xijing Zhang、Wugang Hou、Gang Zhao、Yingfeng Lei、Fanglin Zhang、Hongwei Ma

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Department of Microbiology,School of Basic Medicine,Air Force Medical University,Xi'an,710032,China

Department of Neurology,Xijing Hospital Air Force Medical University,Xi'an,710032,China

Center of Clinical Aerospace Medicine,School of Aerospace Medicine,Key Laboratory of Aerospace Medicine of Ministry of Education,Air Force Medical University,Xi'an,710032,China

Department of Anesthesiology & Critical Care Medicine,Xijing Hospital,Air Force Medical University,Xi'an,710032,China

The College of Life Sciences and Medicine,Northwest University,Xi'an,710069,China

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National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaKey Research and Development Program of ShaanxiKey Research and Development Program of Shaanxi

8217227231970148822223672021ZDLSF01-052021ZDLSF01-02

2023

10.1016/j.virs.2023.08.006

中国病毒学
中国科学院武汉病毒研究所，中国微生物学会

中国病毒学

CSTPCDCSCD
影响因子：0.393
ISSN：1674-0769
年,卷(期)：2023.38(5)
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