MAVS-MKK7-JNK2 defines a novel apoptotic signaling pathway during viral infection

PLoS Pathog. 2014 Mar 20;10(3):e1004020. doi: 10.1371/journal.ppat.1004020. eCollection 2014 Mar.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Apoptosis / immunology*
  • Blotting, Western
  • Humans
  • Immunohistochemistry
  • MAP Kinase Kinase 7 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Mitogen-Activated Protein Kinase 9 / metabolism
  • RNA, Small Interfering
  • Real-Time Polymerase Chain Reaction
  • Respirovirus Infections / immunology*
  • Respirovirus Infections / metabolism
  • Sendai virus / immunology
  • Signal Transduction / immunology*
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • IPS-1 protein, mouse
  • RNA, Small Interfering
  • Mitogen-Activated Protein Kinase 9
  • MAP Kinase Kinase 7
  • Map2k7 protein, mouse

Grant support

This work was supported by grants from National Natural Science Foundation of China (31030021, 31200671, 81161120542), Ministry of Science and Technology of China (2012CB910200, 2011CB910904). YH was supported by China Postdoctoral Science Foundation, K.C. Wong Education Foundation (Hong Kong) and SA-SIBS Scholarship Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.