來自武漢大學(xué)生科院,，中科院武漢病毒研究所，上海交通大學(xué)的研究人員發(fā)表了題為“E3 ligase WWP2 negatively regulates TLR3-mediated innate immune response by targeting TRIF for ubiquitination and degradation”的文章,，通過多方面研究,，發(fā)現(xiàn)了一種含WW結(jié)構(gòu)域的E3泛素蛋白連接酶：WWP2能通過靶向TRIF的泛素化和降解過程，負(fù)調(diào)控TLR3介導(dǎo)的天然免疫和炎癥應(yīng)答作用,。這一研究成果公布在美國《國家科學(xué)院院刊》（PNAS）雜志上,。
文章的通訊作者為王延軼博士，其早年畢業(yè)于北京大學(xué)生命科學(xué)學(xué)院,，曾任武漢大學(xué)講師、副教授,。主要研究方向?yàn)樗拗骺垢腥久庖邞?yīng)答機(jī)制,。先后主持或承擔(dān)過國家自然科學(xué)基金、973等多項(xiàng)課題,。已在Molecular Cell,、PNAS、Cell Research等國際知名刊物發(fā)表SCI論文多篇,。
Toll樣受體（Toll-like receptors ,，TLRs）是一個(gè)廣泛存在于昆蟲、脊椎動(dòng)物和植物中序列高度保守而古老的家族,，它們在天然免疫中可發(fā)揮重要的抗感染免疫功能,，并與免疫耐受、特異性抗感染免疫,，因此參與許多疾病的發(fā)病過程,，除此之外TLRs與傳染病、腫瘤,、心血管病,、自身免疫性疾病,、過敏等都有著密切關(guān)系。它亦是研究和開發(fā)新藥的一個(gè)新的靶點(diǎn),，故受到國際醫(yī)學(xué)生物學(xué)廣泛關(guān)注,。
研究表明，TLR3識(shí)別病毒雙鏈RNA的過程,，能觸發(fā)轉(zhuǎn)錄因子NF-κB和干擾素調(diào)節(jié)因子3的激活,，從而誘導(dǎo)I型干擾素和促炎性細(xì)胞因子的表達(dá)。而干擾素TIR結(jié)構(gòu)域銜接蛋白( TIR-domain-containing adapter-inducing interferon,TRIF)則是TLR3介導(dǎo)的信號(hào)途徑中必需的銜接蛋白,。在這篇文章中,，研究人員發(fā)現(xiàn)了一種靶向TRIF的TLR3介導(dǎo)天然免疫應(yīng)答作用。
研究人員通過生化純化實(shí)驗(yàn),，發(fā)現(xiàn)含WW結(jié)構(gòu)域的E3泛素蛋白連接酶2（E3 ubiquitin ligase WW domain-containing protein 2,，WWP2）是一種TRIF相關(guān)蛋白，能介導(dǎo)K48相關(guān)的TRIF泛素化和降解（TLR3激活后）,。
如果WWP2過量表達(dá),，就會(huì)抑制TLR3介導(dǎo)的NF-κB和干擾素調(diào)節(jié)因子3的激活，而敲除WWP2則會(huì)獲得相反的結(jié)果,。研究人員還利用Wwp2基因缺陷型小鼠,，進(jìn)一步分析了Wwp2在天然免疫應(yīng)答中的作用。結(jié)果他們得到了一致的結(jié)果,。
這些研究結(jié)果表明,，WWP2能通過靶向TRIF的泛素化和降解過程，負(fù)調(diào)控TLR3介導(dǎo)的天然免疫和炎癥應(yīng)答作用,。(生物谷Bioon.com)
doi: 10.1073/pnas.1220271110
PMC:
PMID:
E3 ligase WWP2 negatively regulates TLR3-mediated innate immune response by targeting TRIF for ubiquitination and degradation
Yan Yang, Bing Liao, Suyun Wang, Bingru Yan, Ying Jin, Hong-Bing Shu, and Yan-Yi Wang.
Recognition of viral double-stranded RNA by Toll-like receptor 3 (TLR3) triggers activation of the transcription factors NF-κB and interferon regulated factor 3, leading to induction of type I interferons and proinflammatory cytokines. TIR-domain–containing adapter-inducing interferon-β (TRIF) is an adapter protein required for TLR3-mediated signaling. Here we identified the E3 ubiquitin ligase WW domain-containing protein 2 (WWP2) as a TRIF-associated protein by biochemical purification. WWP2 mediated K48-linked ubiquitination and degradation of TRIF upon TLR3 activation. Overexpression of WWP2 inhibited TLR3-mediated NF-κB and interferon regulated factor 3 activation, whereas knockdown of WWP2 had opposite effects. We generated Wwp2-deficient mice to further investigate the roles of Wwp2 in innate immune responses. Consistently, production of IFN-β, CCL5, TNFα, and IL-6 in response to the TLR3 ligand poly(I:C) was elevated in Wwp2?/? macrophages and Wwp2-deficient mice exhibited increased susceptibility to poly(I:C)-induced death than the control littermates. Our findings suggest that WWP2 negatively regulates TLR3-mediated innate immune and inflammatory responses by targeting TRIF for ubiquitination and degradation.
