O'Prey Jim, Skommer Joanna, Wilkinson Simon, Ryan Kevin M
Tumor Cell Death Laboratory, Beatson Institute for Cancer Research, Bearsden, Glasgow, East Dunbartonshire, UK.
Cell Cycle. 2009 Jul 15;8(14):2260-5. doi: 10.4161/cc.8.14.9050. Epub 2009 Jul 19.
Autophagy is a membrane-trafficking process that serves to deliver cytoplasmic proteins and organelles to the lysosome for degradation. The process is genetically defined and many of the factors involved are conserved from yeast to man. Recently, a number of new autophagy regulators have been defined, including the Damage-Regulated Autophagy Modulator (DRAM), which is a lysosomal protein that links autophagy and the tumor suppressor, p53. We describe here analysis of DRAM-related proteins which reveals evolutionary conservation and divergence of DRAM's role in autophagy. We report that humans have 5 other proteins that show significant homology to DRAM. The closest of these, which we have termed DRAM2, displays 45% identity and 67% conservation when compared to DRAM. Interestingly, although similar to DRAM in terms of homology, DRAM2 is different from DRAM as it not induced by p53 or p73. DRAM2 is also a lysosomal protein, but again unlike DRAM its overexpression does not modulate autophagy. In contrast to humans, the Drosophila genome only encodes one DRAM-like protein, which is approximately equal in similarity to human DRAM and DRAM2. This questions, therefore, whether DRAM function is conserved from fly to man or whether DRAM's capacity to regulate autophagy has evolved in higher eukaryotes. Expression of DmDRAM, however, clearly revealed an ability to modulate autophagy. This points, therefore, to a conserved role of DRAM in this process and that additional human proteins have more recently evolved which, while potentially sharing some similarities with DRAM, may not be as intrinsically connected to autophagy regulation.
自噬是一种膜运输过程，其作用是将细胞质蛋白和细胞器输送到溶酶体进行降解。该过程由基因定义，许多参与其中的因子从酵母到人类都是保守的。最近，已经确定了一些新的自噬调节因子，包括损伤调节自噬调节剂（DRAM），它是一种溶酶体蛋白，将自噬与肿瘤抑制因子p53联系起来。我们在此描述了对DRAM相关蛋白的分析，该分析揭示了DRAM在自噬中的作用在进化上的保守性和差异性。我们报告说，人类还有另外5种与DRAM具有显著同源性的蛋白。其中最接近的一种，我们称之为DRAM2，与DRAM相比，其同一性为45%，保守性为67%。有趣的是，尽管DRAM2在同源性方面与DRAM相似，但它与DRAM不同，因为它不是由p53或p73诱导的。DRAM2也是一种溶酶体蛋白，但同样与DRAM不同的是，其过表达不会调节自噬。与人类不同，果蝇基因组只编码一种类似DRAM的蛋白，其与人类DRAM和DRAM2的相似性大致相同。因此，这就产生了一个问题，即DRAM的功能从果蝇到人类是否保守，或者DRAM调节自噬的能力是否在高等真核生物中进化。然而，DmDRAM的表达清楚地显示出其具有调节自噬的能力。因此，这表明DRAM在这个过程中具有保守作用，并且最近进化出了额外的人类蛋白，这些蛋白虽然可能与DRAM有一些相似之处，但可能与自噬调节没有内在联系。
