Scientific Reports (Aug 2019)

Lyssavirus matrix protein cooperates with phosphoprotein to modulate the Jak-Stat pathway

  • Florian Sonthonnax,
  • Benoit Besson,
  • Emilie Bonnaud,
  • Grégory Jouvion,
  • David Merino,
  • Florence Larrous,
  • Hervé Bourhy

DOI
https://doi.org/10.1038/s41598-019-48507-4
Journal volume & issue
Vol. 9, no. 1
pp. 1 – 13

Abstract

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Abstract Phosphoprotein (P) and matrix protein (M) cooperate to undermine the immune response to rabies virus (RABV) infections. While P is involved in the modulation of the Jak-Stat pathway through the cytoplasmic retention of interferon (IFN)-activated STAT1 (pSTAT1), M interacts with the RelAp43-p105-ABIN2-TPL2 complex, to efficiently inhibit the nuclear factor-κB (NF-κB) pathway. Using transfections, protein-complementation assays, reverse genetics and DNA ChIP, we identified a role of M protein in the control of Jak-Stat signaling pathway, in synergy with the P protein. In unstimulated cells, both M and P proteins were found to interact with JAK1. Upon type-I IFN stimulation, the M switches toward pSTAT1 interaction, which results in an enhanced capacity of P protein to interact with pSTAT1 and restrain it in the cytoplasm. Furthermore, the role for M-protein positions 77, 100, 104 and 110 was also demonstrated in interaction with both JAK1 and pY-STAT1, and confirmed in vivo. Together, these data indicate that M protein cooperates with P protein to restrain in parallel, and sequentially, NF-κB and Jak-Stat pathways.