目前普遍認(rèn)為基因的選擇性剪接即基因選擇不同的剪接位點(diǎn)組合，是機(jī)體增加蛋白多樣性的一種有效方式，也是機(jī)體調(diào)控蛋白表達(dá)的一種重要機(jī)制。在人類和靈長類動(dòng)物中，保守估計(jì)約有75%的基因發(fā)生選擇性剪接，尤其多發(fā)生在免疫系統(tǒng)。一個(gè)的免疫系統(tǒng)必須適時(shí)、適當(dāng)?shù)貙?duì)病原微生物做出免疫應(yīng)答。而免疫應(yīng)答是機(jī)體免疫系統(tǒng)對(duì)抗原刺激所產(chǎn)生的以清除病源微生物為目的的生理過程。
“主要組織相容性復(fù)合物（MHC）是廣泛存在于脊椎動(dòng)物體內(nèi)與免疫功能密切相關(guān)的一組基因群，其基因產(chǎn)物不僅參與移植排斥和T淋巴細(xì)胞的分化發(fā)育，在機(jī)體免疫應(yīng)答的啟動(dòng)和免疫調(diào)節(jié)中也發(fā)揮重要作用。”戴正喜說，“許多研究表明，主要組織相容性復(fù)合物I類基因，在不同物種中均會(huì)發(fā)生不同程度的選擇性剪接，產(chǎn)生新的剪接異構(gòu)體。但幾乎不清楚它怎樣精細(xì)調(diào)控免疫系統(tǒng)。”
為探討剪接異構(gòu)體對(duì)全長型的MHCIA分子的影響及其在免疫調(diào)控中的作用，戴正喜等以人類近親獼猴為模型動(dòng)物，在獼猴外周血中具有單個(gè)核的細(xì)胞中發(fā)現(xiàn)和鑒定了一種新的剪接異構(gòu)體。通過生物化學(xué)和分子生物學(xué)實(shí)驗(yàn)研究發(fā)現(xiàn)：這種新的剪接異構(gòu)體可以表達(dá)于細(xì)胞膜表面，并且它的糖基化模式和蛋白降解速度與全長型的MHCIA分子明顯不同。
更有趣的是，它們倆能在細(xì)胞內(nèi)形成一種全新的異源二聚體結(jié)構(gòu)。進(jìn)一步研究還發(fā)現(xiàn)，此異源復(fù)合體能促進(jìn)MHCIA蛋白的穩(wěn)定性。這種新的順式調(diào)控模式，為理解其對(duì)免疫應(yīng)答的影響提供了一種全新視角。
該項(xiàng)研究獲得專家高度認(rèn)可，他們一致認(rèn)為是主要組織相容性復(fù)合物剪接領(lǐng)域的一項(xiàng)重要進(jìn)展。
原文摘要：
The β2-Microglobulin–Free Heterodimerization of Rhesus Monkey MHC Class I A with Its Normally Spliced Variant Reduces the Ubiquitin-Dependent Degradation of MHC Class I A
Zheng-Xi Dai,Gao-Hong Zhang, Xi-He Zhang, Hou-Jun Xia, Shao-You Li and Yong-Tang Zheng
The MHC class I （MHC I） molecules play a pivotal role in the regulation of immune responses by presenting antigenic peptides to CTLs and by regulating cytolytic activities of NK cells. In this article, we show that MHC I A in rhesus macaques can be alternatively spliced, generating a novel MHC I A isoform （termed “MHC I A-sv1”） devoid of α3 domain. Despite the absence of β2-microglobulin （β2m）, the MHC I A-sv1 proteins reached the cell surface of K562-transfected cells as endoglycosidase H-sensitive glycoproteins that could form disulfide-bonded homodimers. Cycloheximide-based protein chase experiments showed that the MHC I A-sv1 proteins were more stable than the full-length MHC I A in transiently or stably transfected cell lines. Of particular interest, our studies demonstrated that MHC I A-sv1 could form β2m-free heterodimers with its full-length protein in mammalian cells. The formation of heterodimers was accompanied by a reduction in full-length MHC I A ubiquitination and consequent stabilization of the protein. Taken together, these results demonstrated that MHC I A-sv1 and MHC I A can form a novel heterodimeric complex as a result of the displacement of β2m and illustrated the relevance of regulated MHC I A protein degradation in the β2m-free heterodimerization-dependent control, which may have some implications for the MHC I A splice variant in the fine tuning of classical MHC I A/TCR and MHC I A/killer cell Ig-like receptor interactions.
