近期Nature上兩篇論文涉及蛋白酶體在壽命及干細(xì)胞功能中的作用。第一篇論文建立了一個(gè)可能的機(jī)制,，來解釋為什么線蟲中增殖的生殖細(xì)胞的去除會(huì)延長(zhǎng)壽命。有g(shù)lp-1（e2141）突變的線蟲沒有生殖細(xì)胞系,，并將資源重新分配給體細(xì)胞,，這樣就有可能騰出資源來投入到壽命的延長(zhǎng)中。它們的蛋白酶體活性也要增強(qiáng)6倍,，同時(shí)對(duì)“與19S蛋白酶體的rpn-6亞單元和FOXO轉(zhuǎn)錄因子DAF-16的表達(dá)的增加相關(guān)的”受損蛋白的清除也要增多6倍。rpn-6的異位表達(dá)足以延長(zhǎng)壽命和保護(hù)線蟲不受蛋白毒性壓力的影響,，說明rpn-6是在與年齡相關(guān)的蛋白動(dòng)態(tài)平衡失調(diào)中糾正相關(guān)缺陷的一個(gè)候選目標(biāo),。第二篇論文提出這樣一個(gè)假設(shè)：迅速分裂的干細(xì)胞有高蛋白酶體活性,，來通過清除受損蛋白保護(hù)基因組和蛋白酶體的完整性,。人胚胎干細(xì)胞被發(fā)現(xiàn)有高26S/30S蛋白酶體活性,，這種活性在發(fā)生誘導(dǎo)的分化時(shí)會(huì)降低,。“高蛋白酶體活性”是由于19S亞單元 PSMD11/RPN-6的表達(dá)增加以及FOXO4對(duì)其表達(dá)的調(diào)制,，后者是一個(gè)胰島素/IGF-1反應(yīng)性轉(zhuǎn)錄因子和DAF-16的直系同源基因,。（生物谷Bioon.com）
doi:10.1038/nature11315
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RPN-6 determines C. elegans longevity under proteotoxic stress conditions
David Vilchez, Ianessa Morantte, Zheng Liu,1 Peter M. Douglas, Carsten Merkwirth, Ana P. C. Rodrigues, Gerard Manning & Andrew Dillin
Organisms that protect their germ-cell lineages from damage often do so at considerable cost: limited metabolic resources become partitioned away from maintenance of the soma, leaving the ageing somatic tissues to navigate survival amid an environment containing damaged and poorly functioning proteins. Historically, experimental paradigms that limit reproductive investment result in lifespan extension. We proposed that germline-deficient animals might exhibit heightened protection from proteotoxic stressors in somatic tissues. We find that the forced re-investment of resources from the germ line to the soma in Caenorhabditis elegans results in elevated somatic proteasome activity, clearance of damaged proteins and increased longevity. This activity is associated with increased expression of rpn-6, a subunit of the 19S proteasome, by the FOXO transcription factor DAF-16. Ectopic expression of rpn-6 is sufficient to confer proteotoxic stress resistance and extend lifespan, indicating that rpn-6 is a candidate to correct deficiencies in age-related protein homeostasis disorders.
doi:10.1038/nature11468
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Increased proteasome activity in human embryonic stem cells is regulated by PSMD11
David Vilchez, Leah Boyer, Ianessa Morantte, Margaret Lutz, Carsten Merkwirth, Derek Joyce, Brian Spencer, Lesley Page, Eliezer Masliah, W. Travis Berggren, Fred H. Gage & Andrew Dillin
Embryonic stem cells can replicate continuously in the absence of senescence and, therefore, are immortal in culture. Although genome stability is essential for the survival of stem cells, proteome stability may have an equally important role in stem-cell identity and function. Furthermore, with the asymmetric divisions invoked by stem cells, the passage of damaged proteins to daughter cells could potentially destroy the resulting lineage of cells. Therefore, a firm understanding of how stem cells maintain their proteome is of central importance. Here we show that human embryonic stem cells (hESCs) exhibit high proteasome activity that is correlated with increased levels of the 19S proteasome subunit PSMD11 (known as RPN-6 in Caenorhabditis elegans) and a corresponding increased assembly of the 26S/30S proteasome. Ectopic expression of PSMD11 is sufficient to increase proteasome assembly and activity. FOXO4, an insulin/insulin-like growth factor-I (IGF-I) responsive transcription factor associated with long lifespan in invertebrates, regulates proteasome activity by modulating the expression of PSMD11 in hESCs. Proteasome inhibition in hESCs affects the expression of pluripotency markers and the levels of specific markers of the distinct germ layers. Our results suggest a new regulation of proteostasis in hESCs that links longevity and stress resistance in invertebrates to hESC function and identity.
