Antagonism of the Phosphatase PP1 by the Measles Virus V Protein Is Required for Innate Immune Escape of MDA5

Meredith E. Davis, May K. Wang, Linda J. Rennick, Florian Full, Sebastian Gableske, Annelies W. Mesman, Sonja I. Gringhuis, Teunis B.H. Geijtenbeek, W. Paul Duprex, and Michaela U. Gack

Cell Host & Microbe. (2014) 16, 19–30

Speaker: Hsin-Hsin Chen (陳亲亲)                              Time: 13:00~14:00, Dec. 24, 2014

Commentator: Dr. Chia-Yi Yu (余佳益 老師)    Place: Room 601

Abstract:

      Melanoma differentiation-associated gene 5 (MDA5) is an important sensor for antiviral innate immunity, and it can be activated via dephosphorylation of recruitment domains (CARDS) by phosphatase PP1-specifically PP1α and PP1γ isoforms [1]. After MDA5 dephosphorylation, RIG-I-like receptor (RLR) interacts with mitochondrial-localized adaptor molecule MAVS/VISA/IPS-1/Cardif, further triggering IFN-α/β induction [2]. In previous studies, V protein, a virulence factor of paramyxovirus, can inhibit MDA5 activity and later on decreases type I interferon (IFNα-/β) production. However, the underlying mechanism of V protein inhibiting MDA5 remains unclear. In this paper, authors hypothesized that viruses may modulate the balance of phosphorylation/dephosphorylation to prevent MDA5 activation and thus escape innate immune detection. To prove the hypothesis, the authors generated mutant V proteins of measles virus either by deleting PP1 motif at C-terminal region or exchanging amino acid sequences of PP1-binding motif from 288RIWY291 to 288AIAA291 . The results showed that PP1-binding motif in the C-terminal tail region of the MV-V protein is necessary for PP1 binding and suppression of MDA5 CARD dephosphorylation. To further investigate the role of MV-V protein in innate immune escape of MDA5-regulated IFN induction, the authors have generated an rMV that expresses a mutant V protein deficient in PP1 binding. The data obtained has shown that V proteins of measles virus are necessary to inhibit type I IFN induction in MV. In conclusion, PP1α and PP1γ play a role in innate immune activation, and PP1 antagonism is a crucial strategy for virus to escape RLR immune signaling.

References:

1.         Gack, M.U. et al. (2010). Phosphorylation-mediated negative regulation of RIG-I antiviral activity. J. Virol. 84, 3220–3229.

2.         Loo, Y.M. et al. (2011).Immune signaling by RIG-I-like receptors. Immunity 34, 680–692.