Department of Medicine.
Department of Pathology.
J Neurosci. 2014 May 14;34(20):6772-89. doi: 10.1523/JNEUROSCI.0077-14.2014.
The import of acetyl-CoA into the ER lumen by AT-1/SLC33A1 is essential for the N(ε)-lysine acetylation of ER-resident and ER-transiting proteins. A point-mutation (S113R) in AT-1 has been associated with a familial form of spastic paraplegia. Here, we report that AT-1S113R is unable to form homodimers in the ER membrane and is devoid of acetyl-CoA transport activity. The reduced influx of acetyl-CoA into the ER lumen results in reduced acetylation of ER proteins and an aberrant form of autophagy. Mice homozygous for the mutation display early developmental arrest. In contrast, heterozygous animals develop to full term, but display neurodegeneration and propensity to infections, inflammation, and cancer. The immune and cancer phenotypes are contingent on the presence of pathogens in the colony, whereas the nervous system phenotype is not. In conclusion, our results reveal a previously unknown aspect of acetyl-CoA metabolism that affects the immune and nervous systems and the risk for malignancies.
乙酰辅酶 A 通过 AT-1/SLC33A1 导入内质网腔对于内质网驻留蛋白和内质网转运蛋白的 N(ε)-赖氨酸乙酰化至关重要。AT-1 中的一个点突变（S113R）与家族性痉挛性截瘫有关。在这里，我们报告 AT-1S113R 无法在内质网膜上形成同源二聚体，并且缺乏乙酰辅酶 A 转运活性。内质网腔中乙酰辅酶 A 的流入减少导致内质网蛋白的乙酰化减少和异常形式的自噬。该突变的纯合子小鼠显示早期发育停滞。相比之下，杂合子动物发育到足月，但表现出神经退行性变和易感染、炎症和癌症的倾向。免疫和癌症表型取决于群体中病原体的存在，而神经系统表型则不是。总之，我们的结果揭示了乙酰辅酶 A 代谢的一个以前未知的方面，它影响免疫系统和神经系统以及恶性肿瘤的风险。
