北京大学蒋争凡老师课题组的论文“PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4” 于11月1日在自然免疫学（Nature Immunology）发表。该项工作发现并证明细胞存在一条由PCBP2-AIP4介导的蛋白质降解途径，特异性负调控固有免疫过程中关键分子MAVS/VISA/IPS1/Cardif的蛋白水平，以降低或避免病源微生物感染引发的机体过度反应。
首先，他们发现PCBP2蛋白可特异性结合MAVS/VISA，从而下调或抑制细胞通过Mda5/RIG-I通路的抗感染反应；PCBP2与MAVS共定位于线粒体，其C端Linker区域与MAVS的跨膜区对于二者之间形成蛋白质复合物是必要的；PCBP2的上调或过表达可特异性引发MAVS蛋白的降解进而抑制I型干扰素的产生。将PCBP2通过RNA干扰技术下调其表达之后，能够显著增强抗病毒免疫反应中I型干扰素的产生；他们进一步的研究发现PCBP2通过泛素化-蛋白酶体途径介导了MAVS的降解，MAVS蛋白中两个赖氨酸的突变能够显著影响MAVS本身的泛素化及降解；在PCBP2蛋白中找到了三个可能的与泛素化E3连接酶结合的序列，并证明其中的第二序列对于MAVS的降解是必须的，突变其中两个保守的氨基酸能抑制MAVS的降解；最后，他们找到了能特异地和PCBP2相互作用的泛素化E3连接酶AIP4。AIP4在PCBP2帮助下与MAVS结合并使之泛素化进而降解MAVS。AIP4-/-的MEF细胞对病毒感染表现出非常过度的固有免疫反应，持续产生过量的I型干扰素与多种炎症反应因子，而后者是导致机体罹患自身免疫病与多器官慢性炎症的罪魁祸首，也是AIP4缺陷性小鼠的重要表型。造成这种免疫调控失调的原因是由于AIP4的缺陷导致MAVS激活后不能被降解，从而使病源微生物感染导致的细胞抗感染反应被持续激活，不被关闭。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature Immunology 10, 1300 - 1308 (2009) 1 November 2009 | doi:10.1038/ni.1815
PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4
Fuping You1, Hui Sun1, Xiang Zhou1, Wenxiang Sun1, Shimin Liang1, Zhonghe Zhai1 & Zhengfan Jiang1
MAVS is critical in innate antiviral immunity as the sole adaptor for RIG-I-like helicases. MAVS regulation is essential for the prevention of excessive harmful immune responses. Here we identify PCBP2 as a negative regulator in MAVS-mediated signaling. Overexpression of PCBP2 abrogated cellular responses to viral infection, whereas knockdown of PCBP2 exerted the opposite effect. PCBP2 was induced after viral infection, and its interaction with MAVS led to proteasomal degradation of MAVS. PCBP2 recruited the HECT domain–containing E3 ligase AIP4 to polyubiquitinate and degrade MAVS. MAVS was degraded after viral infection in wild-type mouse embryonic fibroblasts but remained stable in AIP4-deficient (Itch-/-) mouse embryonic fibroblasts, coupled with greatly exaggerated and prolonged antiviral responses. The PCBP2-AIP4 axis defines a new signaling cascade for MAVS degradation and 'fine tuning' of antiviral innate immunity.
1 The Education Ministry Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China.
