Premature translational termination products are rapidly degraded substrates for MHC class I presentation.
Premature translational termination products are rapidly degraded substrates for MHC class I presentation.
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DOI：
10.1371/journal.pone.0051968
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Nicchitta CV
中科院分区：
文献类型：
--
作者：
Lacsina JR;Marks OA;Liu X;Reid DW;Jagannathan S;Nicchitta CV
近30%的新合成的多肽被靶向用于快速蛋白酶体介导的降解。这些快速降解的多肽（RDP）是MHC I类呈递途径的抗原底物来源，允许细胞毒性T淋巴细胞对新合成的蛋白质进行免疫监视。尽管RDPs在MHC I呈递中的作用已被公认，但仍不清楚RDPs与其更稳定的对应物的分子特征。有人提出，提前翻译终止产物可能构成RDP的一种形式;事实上，在原核生物中，翻译脱落产物是蛋白质合成的正常副产物，随后迅速降解。为了研究提前终止产物的细胞命运，我们使用抗生素嘌呤霉素作为一种手段来实验性地操纵人类细胞中提前终止的多肽产生。在低浓度下，嘌呤霉素增加了进入快速降解多肽池的通量，小多肽比高分子量嘌呤霉素加合物明显更不稳定。使用抗嘌呤霉素抗血清的免疫沉淀实验表明，大多数肽基嘌呤霉素以蛋白酶体依赖性方式快速降解。低浓度的嘌呤霉素增加了细胞表面MHC I-肽复合物的回收率，表明可以通过MHC I途径加工提前终止的多肽以进行呈递。然而，在嘌呤霉素的持续存在下，MHC I出口到细胞表面被抑制，与聚泛素化蛋白的积累一致。嘌呤霉素的时间和剂量依赖性效应表明，肽基嘌呤霉素加合物的库在它们对各种蛋白水解途径的靶向上不同，而这些蛋白水解途径又在它们进入MHC I呈递机制的效率上不同。这些研究强调了细胞蛋白水解途径的多样性，这些途径对于过早终止的多肽的代谢和免疫监视是必要的，这些多肽本质上是高度异质的。
Nearly thirty percent of all newly synthesized polypeptides are targeted for rapid proteasome-mediated degradation. These rapidly degraded polypeptides (RDPs) are a source of antigenic substrates for the MHC class I presentation pathway, allowing for immunosurveillance of newly synthesized proteins by cytotoxic T lymphocytes. Despite the recognized role of RDPs in MHC I presentation, it remains unclear what molecular characteristics distinguish RDPs from their more stable counterparts. It has been proposed that premature translational termination products may constitute a form of RDP; indeed, in prokaryotes translational drop-off products are normal by-products of protein synthesis and are subsequently rapidly degraded. To study the cellular fate of premature termination products, we used the antibiotic puromycin as a means to experimentally manipulate prematurely terminated polypeptide production in human cells. At low concentrations, puromycin enhanced flux into rapidly degraded polypeptide pools, with small polypeptides being markedly more labile then high molecular weight puromycin adducts. Immunoprecipitation experiments using anti-puromycin antisera demonstrated that the majority of peptidyl-puromycins are rapidly degraded in a proteasome-dependent manner. Low concentrations of puromycin increased the recovery of cell surface MHC I-peptide complexes, indicating that prematurely terminated polypeptides can be processed for presentation via the MHC I pathway. In the continued presence of puromycin, however, MHC I export to the cell surface was inhibited, coincident with the accumulation of polyubiquitinated proteins. The time- and dose-dependent effects of puromycin suggest that the pool of peptidyl-puromycin adducts differ in their targeting to various proteolytic pathways that, in turn, differ in the efficiency with which they access the MHC I presentation machinery. These studies highlight the diversity of cellular proteolytic pathways necessary for the metabolism and immunosurveillance of prematurely terminated polypeptides that are, by their nature, highly heterogeneous.
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影响因子：
8
作者：
Dolan, Brian P.;Bennink, Jack R.;Yewdell, Jonathan W.
通讯作者：
Yewdell, Jonathan W.
DOI：
10.1073/pnas.94.15.8064
发表时间：
1997-07-22
影响因子：
11.1
作者：
Day, PM;Yewdell, JW;Bennink, JR
通讯作者：
Bennink, JR
影响因子：
11.4
作者：
Huang, Lan;Kuhls, Matthew C.;Eisenlohr, Laurence C.
通讯作者：
Eisenlohr, Laurence C.
影响因子：
4.8
作者：
Qian, Shu-Bing;Zhang, Xingqian;Patterson, Cam
通讯作者：
Patterson, Cam
影响因子：
7.8
作者：
McCallum, CD;Do, H;Frydman, J
通讯作者：
Frydman, J