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

• Published in: Scientific reports 2019-08, Vol.9 (1), p.12171-13, Article 12171
• Main Authors: Sonthonnax, Florian, Besson, Benoit, Bonnaud, Emilie, Jouvion, Grégory, Merino, David, Larrous, Florence, Bourhy, Hervé
• Format: Article
• Language: English
• Subjects: 13; 13/51; 14/63; 38/70; 38/90; 631/326/596/2555; 631/326/596/2557; 631/326/596/2558; 82/1; 82/29; Animals; Cell Behavior; Cellular Biology; Complementation; Cytoplasm; Cytoplasm - metabolism; HeLa Cells; Humanities and Social Sciences; Humans; Immune response; Immunity, Innate; Interferon; Interferon Type I - metabolism; Janus kinase; Janus Kinase 1 - metabolism; Life Sciences; Lyssavirus; Lyssavirus - metabolism; Lyssavirus - pathogenicity; M protein; Matrix protein; Mice; Mice, Inbred BALB C; multidisciplinary; Mutagenesis, Site-Directed; NF-kappa B - metabolism; NF-κB protein; P protein; Phosphoproteins - genetics; Phosphoproteins - metabolism; Promoter Regions, Genetic; Proteins; Rabies; Science; Science (multidisciplinary); Signal Transduction; Stat1 protein; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Th2 Cells - immunology; Th2 Cells - metabolism; Viral Matrix Proteins - genetics; Viral Matrix Proteins - metabolism; Viral Proteins - genetics; Viral Proteins - metabolism; Virulence
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-48507-4

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.