北京大學蔣爭凡老師課題組的論文“PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4” 于11月1日在自然免疫學（Nature Immunology）發(fā)表。該項工作發(fā)現(xiàn)并證明細胞存在一條由PCBP2-AIP4介導的蛋白質(zhì)降解途徑,，特異性負調(diào)控固有免疫過程中關鍵分子MAVS/VISA/IPS1/Cardif的蛋白水平,，以降低或避免病源微生物感染引發(fā)的機體過度反應。
首先,，他們發(fā)現(xiàn)PCBP2蛋白可特異性結(jié)合MAVS/VISA，從而下調(diào)或抑制細胞通過Mda5/RIG-I通路的抗感染反應,；PCBP2與MAVS共定位于線粒體,，其C端Linker區(qū)域與MAVS的跨膜區(qū)對于二者之間形成蛋白質(zhì)復合物是必要的；PCBP2的上調(diào)或過表達可特異性引發(fā)MAVS蛋白的降解進而抑制I型干擾素的產(chǎn)生,。將PCBP2通過RNA干擾技術下調(diào)其表達之后,，能夠顯著增強抗病毒免疫反應中I型干擾素的產(chǎn)生；他們進一步的研究發(fā)現(xiàn)PCBP2通過泛素化-蛋白酶體途徑介導了MAVS的降解,，MAVS蛋白中兩個賴氨酸的突變能夠顯著影響MAVS本身的泛素化及降解,；在PCBP2蛋白中找到了三個可能的與泛素化E3連接酶結(jié)合的序列，并證明其中的第二序列對于MAVS的降解是必須的,，突變其中兩個保守的氨基酸能抑制MAVS的降解,；最后，他們找到了能特異地和PCBP2相互作用的泛素化E3連接酶AIP4,。AIP4在PCBP2幫助下與MAVS結(jié)合并使之泛素化進而降解MAVS,。AIP4-/-的MEF細胞對病毒感染表現(xiàn)出非常過度的固有免疫反應，持續(xù)產(chǎn)生過量的I型干擾素與多種炎癥反應因子，而后者是導致機體罹患自身免疫病與多器官慢性炎癥的罪魁禍首,，也是AIP4缺陷性小鼠的重要表型,。造成這種免疫調(diào)控失調(diào)的原因是由于AIP4的缺陷導致MAVS激活后不能被降解，從而使病源微生物感染導致的細胞抗感染反應被持續(xù)激活,，不被關閉,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
