中科院昆明動物研究所鄭永唐研究小組首次發(fā)現(xiàn),，主要組織相容性復(fù)合物基因通過選擇不同的剪接位點產(chǎn)生了一種新的存在形式,，可調(diào)控免疫系統(tǒng),。該成果已發(fā)表于國際期刊《免疫學(xué)期刊》上。
據(jù)戴正喜介紹,，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組合,，是機體增加蛋白多樣性的一種有效方式，也是機體調(diào)控蛋白表達的一種重要機制。在人類和靈長類動物中,，保守估計約有75%的基因發(fā)生選擇性剪接,，尤其多發(fā)生在免疫系統(tǒng)。一個高效的免疫系統(tǒng)必須適時,、適當(dāng)?shù)貙Σ≡⑸镒龀雒庖邞?yīng)答,。而免疫應(yīng)答是機體免疫系統(tǒng)對抗原刺激所產(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淋巴細胞的分化發(fā)育,，在機體免疫應(yīng)答的啟動和免疫調(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調(diào)控免疫系統(tǒng)。”
為探討剪接異構(gòu)體對全長型的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物,，在獼猴外周血中具有單個核的細胞中發(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)實驗研究發(fā)現(xiàn)：這種新的剪接異構(gòu)體可以表達于細胞膜表面,，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，它們倆能在細胞內(nèi)形成一種全新的異源二聚體結(jié)構(gòu),。進一步研究還發(fā)現(xiàn),，此異源復(fù)合體能促進MHCIA蛋白的穩(wěn)定性。這種新的順式調(diào)控模式,，為理解其對免疫應(yīng)答的影響提供了一種全新視角,。
該項研究獲得國際專家高度認(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)域的一項重要進展,。（生物谷 bioon.com）
doi:10.4049/jimmunol.1100665
PMC:
PMID:
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.
