UBB+1-induced activation of autophagy reduces cytotoxicity of amyloid-β in yeast

UBB+1 is a mutated version of ubiquitin B caused by a transcriptional frameshift. The accumulation of UBB+1, has been linked to ubiquitin-proteasome system (UPS) dysfunction and neurodegeneration. Alzheimer’s disease (AD) is the most common form of neurodegeneration and accumulation of amyloid β (Aβ) in the brain is a prominent neuropathological feature of AD. In our previous study, we found that low expression of UBB+1 could protect cells against several stresses during chronological aging. Here, we applied the genome-wide expression analyses and found that low UBB+1 expression activated the autophagy pathway. Low UBB+1 expression was shown to upregulate vacuolar activity and promote transport of the ATG8p (autophagic marker) to the vacuole. To further study the effects, we expressed low level of UBB+1 in our humanized yeast Aβ models with the expression of either Aβ42 or Aβ40. Interestingly, the co-expression of UBB+1 with Aβ42 or Aβ40 showed a reduction of intracellular Aβ levels and increased chronological life span. In the autophagy deficient mutant background (atg1∆), the intracellular Aβ levels were not affected by UBB+1 expression. Our findings suggest a mechanism of UBB+1 action in reducing intracellular levels of Aβ.UBB+1是由转录移码突变导致的泛素B（ubiquitin B）突变体。UBB+1的积累与泛素-蛋白酶体系统（ubiquitin-proteasome system, UPS）功能异常及神经退行性病变密切相关。阿尔茨海默病（Alzheimer’s disease, AD）是最常见的神经退行性疾病，大脑内β淀粉样蛋白（amyloid β, Aβ）的沉积是AD显著的神经病理特征。在既往研究中，我们发现低表达UBB+1可在细胞时序衰老过程中抵御多种应激。本研究通过全基因组表达分析发现，低水平UBB+1表达可激活自噬通路。进一步实验显示，低UBB+1表达能够上调液泡活性，并促进自噬标志物ATG8p（autophagic marker）向液泡的转运。为深入探究其作用效应，我们在分别表达Aβ42或Aβ40的人源化酵母Aβ模型中低表达UBB+1。有趣的是，UBB+1与Aβ42或Aβ40共表达可降低细胞内Aβ水平，并延长细胞时序寿命。在自噬缺陷突变体背景（atg1∆）中，UBB+1的表达对细胞内Aβ水平无显著影响。本研究结果提示了UBB+1降低细胞内Aβ水平的作用机制。