Davis Meredith E, Wang May K, Rennick Linda J, Full Florian, Gableske Sebastian, Mesman Annelies W, Gringhuis Sonja I, Geijtenbeek Teunis B H, Duprex W Paul, Gack Michaela U
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Microbiology Division, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA.
Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA.
Cell Host Microbe. 2014 Jul 9;16(1):19-30. doi: 10.1016/j.chom.2014.06.007.
The cytosolic sensor MDA5 is crucial for antiviral innate immune defense against various RNA viruses including measles virus; as such, many viruses have evolved strategies to antagonize the antiviral activity of MDA5. Here, we show that measles virus escapes MDA5 detection by targeting the phosphatases PP1α and PP1γ, which regulate MDA5 activity by removing an inhibitory phosphorylation mark. The V proteins of measles virus and the related paramyxovirus Nipah virus interact with PP1α/γ, preventing PP1-mediated dephosphorylation of MDA5 and thereby its activation. The PP1 interaction with the measles V protein is mediated by a conserved PP1-binding motif in the C-terminal region of the V protein. A recombinant measles virus expressing a mutant V protein deficient in PP1 binding is unable to antagonize MDA5 and is growth impaired due to its inability to suppress interferon induction. This identifies PP1 antagonism as a mechanism employed by paramyxoviruses for evading innate immune recognition.
胞质传感器黑色素瘤分化相关基因5（MDA5）对于抵抗包括麻疹病毒在内的多种RNA病毒的抗病毒天然免疫防御至关重要；因此，许多病毒已经进化出对抗MDA5抗病毒活性的策略。在此，我们表明麻疹病毒通过靶向磷酸酶PP1α和PP1γ来逃避MDA5的检测，PP1α和PP1γ通过去除抑制性磷酸化标记来调节MDA5的活性。麻疹病毒和相关副粘病毒尼帕病毒的V蛋白与PP1α/γ相互作用，阻止PP1介导的MDA5去磷酸化，从而阻止其激活。PP1与麻疹V蛋白的相互作用由V蛋白C末端区域中保守的PP1结合基序介导。表达缺乏PP1结合的突变V蛋白的重组麻疹病毒无法对抗MDA5，并且由于其无法抑制干扰素诱导而生长受损。这确定了PP1拮抗作用是副粘病毒用于逃避天然免疫识别的一种机制。
