近期,，中科院武漢病毒研究所王漢中課題組在人博卡病毒（HBoV）調(diào)控宿主天然免疫反應(yīng)機(jī)制的研究中取得重要進(jìn)展,。研究表明，HBoV的結(jié)構(gòu)蛋白VP2能夠通過抑制I型干擾素通路上的負(fù)反饋調(diào)節(jié)因子RNF125來增強(qiáng)IFN-b生成,。相關(guān)結(jié)果已發(fā)表于國際免疫學(xué)期刊The Journal of Immunology上,。
大量的臨床研究表明，HBoV主要感染兩歲以下的嬰幼兒,，并常與其它呼吸道病毒混合感染,。HBoV陽性的患者常伴隨呼吸道疾病與腸道疾病，盡管已經(jīng)報(bào)道了至少兩例HBoV單一感染致死性病例,，但目前尚無證據(jù)表明HBoV能夠致病,。HBoV入侵常引起宿主普遍的體液免疫及細(xì)胞免疫反應(yīng)，但其如何調(diào)控宿主天然免疫的研究甚少,。本課題組發(fā)現(xiàn)在仙臺(tái)病毒（SeV）或Poly(dA-dT)刺激后,，HBoV的VP2能夠通過IRF3通路增強(qiáng)IFN-b的生成。其主要機(jī)制為：VP2與RIG-I的負(fù)反饋調(diào)節(jié)因子RNF125結(jié)合并抑制RNF125介導(dǎo)的RIG-I的泛素化降解,，從而導(dǎo)致IFN-b持續(xù)產(chǎn)生,。
本研究揭示了HBoV調(diào)控宿主免疫反應(yīng)的新機(jī)制,，并具體闡述了一種病毒基因表達(dá)導(dǎo)致的IRF3信號(hào)異常激活的機(jī)制，從而為研究HBoV的致病機(jī)理提供理論依據(jù),。
該研究得到了國家“973”項(xiàng)目和國家自然科學(xué)基金的支持,。（生物谷Bioon.com）
doi:10.4049/jimmunol.1202933
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PMID:
Human Bocavirus VP2 Upregulates IFN-β Pathway by Inhibiting Ring Finger Protein 125–Mediated Ubiquitination of Retinoic Acid–Inducible Gene-I
Huanle Luo*, Zhenfeng Zhang*, Zhenhua Zheng*, Xianliang Ke*, Xiaowei Zhang*, Qian Li*, Yan Liu*, Bingke Bai†, Panyong Mao†, Qinxue Hu* and Hanzhong Wang*
Precise regulation of innate immunity is crucial for maintaining optimal immune responses against infections. Whereas positive regulation of IFN signaling elicits rapid type I IFNs, negative regulation is equally important in preventing the production of superfluous IFNs that can be hazardous to the host. The positive regulators of IFN pathway are known to be the main targets of viruses to antagonize the innate immune system. Whether viruses target the negative regulators of IFN pathway remains to be fully investigated. In this study, we report that the structural protein VP2 of human Bocavirus modulates IFN pathway by targeting the ring finger protein 125 (RNF125), a negative regulator of type I IFN signaling, which conjugates Lys48-linked ubiquitination to retinoic acid–inducible gene-I (RIG-I) and subsequently leads to the proteasome-dependent degradation of RIG-I. VP2 not only upregulated Sendai virus (SeV)–induced IFNB promoter activity, but also enhanced SeV-induced IFN-β production at both mRNA and protein levels. In agreement, the level of Ser396-phosphorylated IFN regulatory factor 3 stimulated by SeV was enhanced in the presence of VP2. Furthermore, VP2 was demonstrated to physically interact with RNF125, resulting in the reduction of RNF125-mediated ubiquitination and proteasome-dependent degradation of RIG-I. Additional study indicated that endogenous RIG-I degradation was decreased in VP2-expressing cells. Our study delineates a unique phenomenon for aberrant activation of IFN regulatory factor 3 pathway and may represent a new mechanism underlying viral manipulation of the host immune system.
