Research Article: MAVS-MKK7-JNK2 Defines a Novel Apoptotic Signaling Pathway during Viral Infection

Date Published: March 20, 2014

Publisher: Public Library of Science

Author(s): Yuefeng Huang, Heng Liu, Senlin Li, Yijun Tang, Bo Wei, Huansha Yu, Chen Wang, Volker Thiel.

http://doi.org/10.1371/journal.ppat.1004020

Abstract

Viral infection induces innate immunity and apoptosis. Apoptosis is an effective means to sacrifice virus-infected host cells and therefore restrict the spread of pathogens. However, the underlying mechanisms of this process are still poorly understood. Here, we show that the mitochondrial antiviral signaling protein (MAVS/VISA/Cardif/IPS-1) is critical for SeV (Sendai virus)-induced apoptosis. MAVS specifically activates c-Jun N-terminal kinase 2 (JNK2) but not other MAP kinases. Jnk2−/− cells, but not Jnk1−/− cells, are unable to initiate virus-induced apoptosis and SeV further fails to trigger apoptosis in MAPK kinase 7 (MKK7) knockout (Mkk7−/−) cells. Mechanistically, MAVS recruits MKK7 onto mitochondria via its 3D domain, which subsequently phosphorylates JNK2 and thus activates the apoptosis pathway. Consistently, Jnk2−/− mice, but not Jnk1−/− mice, display marked inflammatory injury in lung and liver after viral challenge. Collectively, we have identified a novel signaling pathway, involving MAVS-MKK7-JNK2, which mediates virus-induced apoptosis and highlights the indispensable role of mitochondrial outer membrane in host defenses.

Partial Text

The induction of innate immunity upon viral infection represents the first line of host defense against microbe invasion. During infection with a RNA virus, the mitochondrial antiviral signaling protein (MAVS/VISA/Cardif/IPS-1) has been recently uncovered to seed a critical protein complex on the mitochondrial outer membrane [1]–[4]. This signalosome consists of TNFR-associated factors (TRAF2/3/6) [5], TNFR-associated death domain protein (TRADD) [6], translocase of outer mitochondrial membrane 70 (TOM70) [7], ubiquitously expressed transcript (UXT-V1) [8], Autophagy proteins (Atg5/Atg12) [9], Mitofusin-2 (Mfn2) [10]et.al. The MAVS signalosome activates TANK-binding kinase 1 (TBK1), which then phosphorylates interferon (IFN) regulatory factor 3(IRF3). In addition, the MAVS signalosome can also activate the IκB kinase (IKK) complex and nuclear factor κB (NF-κB). Synergistically, these transcription factors (IRF3 and NF-κB) induce the early production of type I interferons and inflammatory cytokines [11].

Viral infection induces innate immunity and apoptosis, which represent effective means for the host to restrict the spread of microbial pathogens. The essential function of MAVS has been well documented in mediating RIG-I/MDA5 innate immune signaling. In this work, we demonstrate that MAVS is also critical for cell apoptosis upon viral infection and highlight the dual function of MAVS in innate immunity and apoptosis.

 

Source:

http://doi.org/10.1371/journal.ppat.1004020

 

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