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A novel contribution of autophagic proteins to the process of cell death.

机译：自噬蛋白对细胞死亡过程的新贡献。

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摘要

Background. Autophagocytosis, also known as a "self eating process" is a mechanism that is primarily used by eukaryotic cells to recycle nutrients rapidly at the onset of environmental stresses such as amino acid or nitrogen starvation. Despite the fact that this process has been known for a number of decades, its mechanism of action remains poorly described. One of the biggest challenges facing this field is the relationship between this "pro-life" phenomenon and the increasingly indisputable evidence linking autophagy and cell death. One of the reasons autophagic cell death (ACD) is questioned is that many of the examples supporting it were obtained using mutants with defects in normal cell death pathways, while many of the examples showing that ACD could be prevented used inhibitors that also affected other processes. One way to resolve this controversy is to develop a new model for studying ACD that can be manipulated genetically. One candidate organism for such studies is Saccharomyces cerevisiae. Since autophagy plays many roles in eukaryotic cell and human pathologies, the results from this analysis could identify novel pathways and gene targets leading to the development of new drugs and treatments.;Methods. In order to examine autophagy functions in response to different stresses I have performed phenotypic analyses on 112 specifically chosen yeast deletion mutants. To distinguish between apoptosis and necrosis I used Annexin V/PI co-staining. Genetic screening for suppressors of cell death identified the yeast vacuolar protein sorting 70 (VPS70) and other members of the transferrin receptor-like protein family (TfRL) including the plant altered meristem program 1 (AMP1) and human prostate specific membrane antigen (PSMA). By means of biochemical examination employing western blot analysis together with changes in the in vivo localization of fluorescent reporters, I monitored how different autophagy pathways are influenced by death-inducing treatments and how the presence of TfRLs are able to alter this response.;Results. As a result of these analyses I first determined that yeast treated with zinc underwent a form of necrosis as they died that was facilitated by a group of autophagy proteins. Secondly, this same treatment also induced other autophagy proteins to carry out a process in opposition to the "pro-death" set so as to prolong yeast survival. Thirdly, I have shown that these two processes also operated when cells were exposed to other stresses such as nitrogen or leucine starvation. Finally, apoptosis and necrosis could be suppressed by any one of three TfRLs including the mammalian Psma.;Conclusions. Based on data I have gathered, I have concluded that Psma and other tested members of the TfRL family possess in common a novel biological activity which can prolong cell survival during exposure to several unrelated stresses. Significantly, none of the experiments found evidence of ACD operating independently of apoptosis and necrosis.
机译：背景。自噬作用，也称为“自食过程”，是一种机制，主要由真核细胞用于在环境应激（例如氨基酸或氮饥饿）发作时快速回收营养。尽管已经知道该过程数十年了，但对其作用机理的描述却很少。该领域面临的最大挑战之一是这种“亲寿”现象与将自噬与细胞死亡联系起来的越来越无可争议的证据之间的关系。质疑自噬细胞死亡（ACD）的原因之一是，许多支持自噬细胞死亡的实例是使用正常细胞死亡途径中存在缺陷的突变体获得的，而许多实例表明，可以使用也可影响其他进程的抑制剂来预防ACD 。解决此争议的一种方法是开发一种新的研究ACD的模型，该模型可以进行基因操作。用于此类研究的一种候选生物是酿酒酵母。由于自噬在真核细胞和人类病理中起着许多作用，因此该分析的结果可以鉴定出导致新药和新疗法开发的新途径和基因靶标。为了检查响应不同压力的自噬功能，我已经对112种特别选择的酵母缺失突变体进行了表型分析。为了区分凋亡和坏死，我使用膜联蛋白V / PI共染色。对细胞死亡抑制剂的基因筛选确定了酵母液泡蛋白分选70（VPS70）和转铁蛋白受体样蛋白家族（TfRL）的其他成员，包括植物改变的分生组织程序1（AMP1）和人前列腺特异膜抗原（PSMA） 。通过采用蛋白质印迹分析的生化检查以及荧光报告基因的体内定位变化，我监测了诱导死亡的处理如何影响不同的自噬途径以及TfRLs的存在如何改变这种反应。这些分析的结果是，我首先确定用锌处理的酵母在死亡时会发生某种形式的坏死，这是由一组自噬蛋白促进的。其次，这种相同的处理还诱导其他自噬蛋白进行与“亲死亡”相反的过程，从而延长酵母的存活。第三，我已经表明，当细胞暴露于其他压力（例如氮或亮氨酸饥饿）时，这两个过程也起作用。最后，凋亡和坏死可以被包括哺乳动物Psma在内的三种TfRL中的任何一种抑制。根据我收集到的数据，我得出结论，Psma和TfRL家族的其他经过测试的成员共同拥有一种新颖的生物活性，可以在暴露于几种无关的压力下延长细胞存活。值得注意的是，没有实验发现ACD的运作独立于细胞凋亡和坏死。

著录项

  • 作者

    Dziedzic, Slawomir A.;

  • 作者单位

    University of Idaho.;

  • 授予单位 University of Idaho.;
  • 学科 Biology Genetics.;Biology Cell.;Biology Microbiology.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 174 p.
  • 总页数 174
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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