近期Nature上两篇论文涉及蛋白酶体在寿命及干细胞功能中的作用。第一篇论文建立了一个可能的机制，来解释为什么线虫中增殖的生殖细胞的去除会延长寿命。有glp-1（e2141）突变的线虫没有生殖细胞系，并将资源重新分配给体细胞，这样就有可能腾出资源来投入到寿命的延长中。它们的蛋白酶体活性也要增强6倍，同时对“与19S蛋白酶体的rpn-6亚单元和FOXO转录因子DAF-16的表达的增加相关的”受损蛋白的清除也要增多6倍。rpn-6的异位表达足以延长寿命和保护线虫不受蛋白毒性压力的影响，说明rpn-6是在与年龄相关的蛋白动态平衡失调中纠正相关缺陷的一个候选目标。第二篇论文提出这样一个假设：迅速分裂的干细胞有高蛋白酶体活性，来通过清除受损蛋白保护基因组和蛋白酶体的完整性。人胚胎干细胞被发现有高26S/30S蛋白酶体活性，这种活性在发生诱导的分化时会降低。“高蛋白酶体活性”是由于19S亚单元 PSMD11/RPN-6的表达增加以及FOXO4对其表达的调制，后者是一个胰岛素/IGF-1反应性转录因子和DAF-16的直系同源基因。（生物谷Bioon.com）
doi:10.1038/nature11315
PMC:
PMID:
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
PMC:
PMID:
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.
