ATase1 and ATase2, proteostasis, and neurological diseases

ATase1 和 ATase2、蛋白质稳态和神经系统疾病

• 批准号: 10554962
• 负责人: Luigi Puglielli
• 金额: $ 30.03万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554962
• 关键词: Acetyl Coenzyme A; Acetylation; Acetyltransferase; Animals; Autophagocytosis; Biochemical; Biological Process; Biology; Brain; Cellular biology; Cessation of life; Collaborations; Communication; Deacetylase; Defect; Developmental Delay Disorders; Endoplasmic Reticulum; Ensure; Equilibrium; Event; Functional disorder; Gene Duplication; Genetic; Glutamate-ammonia-ligase adenylyltransferase; Glycoproteins; Goals; Golgi Apparatus; Heterozygote; Human; Intellectual functioning disability; Laboratories; Lysine; Maintenance; Mass Spectrum Analysis; Mediating; Membrane Transport Proteins; Metabolic; Modeling; Molecular; Molecular Biology; Mus; Mutation; Neurons; Neuropathy; Organelles; Output; Pathway interactions; Peripheral; Phenotype; Progeria; Proteins; Quality Control; Research; Series; Techniques; Testing; Therapeutic; autism spectrum disorder; design; disease phenotype; experimental study; human disease; in vivo; loss of function; mouse model; nervous system disorder; novel; pharmacologic; premature; protein aggregation; proteostasis; response; trafficking; translational approach

We discovered that Nε-lysine acetylation occurs in the lumen of the endoplasmic reticulum (ER) in 2007. From that initial finding, we went on to discover the entire ER acetylation machinery (one membrane transporter, AT-1/SLC33A1, and two acetyltranferases, ATase1 and ATase2) and uncover a novel piece of ER biology. Specifically, we discovered that the ER acetylation machinery regulates proteostasis within the secretory pathway as well as metabolic crosstalk between different intracellular organelles and compartments. Human-based studies discovered that dysfunctional ER acetylation, as caused by loss-of-function homozygous and heterozygous mutations or gene duplication events, is associated with different human diseases, from developmental delay of the brain and premature death to peripheral forms of neuropathy, autism spectrum disorder, intellectual disability and segmental progeria. Mouse models that mimic these genetic events recapitulate associated human diseases. Importantly, ATase-targeting compounds that restore the proteostatic functions of the ER rescue the disease phenotypes of the animals. In conclusion, we have identified a novel molecular machinery that is key to the maintenance of proteostasis within the secretory pathway, and that can be targeted to (i) understand the pathophysiology of several related neurological diseases and (ii) develop appropriate translational approaches to resolve proteostatic defects. The GENERAL HYPOTHESIS of this research is that ATase1 and ATase2 act downstream of an intracellular communication network that regulates the proteostatic functions of the ER and secretory pathway. Our main goal is to dissect the molecular mechanism(s) underlying the acetyl-CoA:lysine acetyltransferase activity of the ATases and understand how ER-based acetylation regulates the efficiency of the secretory pathway. Aim 1 will test the hypothesis that the ATases have divergent functions and differentially regulate proteostasis and metabolic crosstalk. Aim 2 will test the hypothesis that unique structural features allow the ATases to respond to acetyl-CoA influx, Ca++ levels, and perturbations in ER proteostasis. Aim 3 will test the hypothesis that the acetyl group added in the ER lumen by the ATases must be removed in the lumen of the Golgi apparatus by Amfion/GDAC to ensure correct trafficking of nascent glycoproteins and the quality of the secretome. In conclusion, this proposal is based on novel findings from our laboratory and offers a series of highly mechanistic studies that have the potential to define new avenues of research (and treatment) for different neurological diseases. The proposal will use unique mouse models as well as highly integrated novel experimental approaches. We believe that upon completion of these studies, we will have defined an entirely new avenue of research for different neurological diseases.

我们在2007年发现了在内质网（ER）管腔内发生的nε -赖氨酸乙酰化。从最初的发现开始，我们继续发现整个内质网乙酰化机制（一个膜转运蛋白，AT-1/SLC33A1，两个乙酰转移酶，ATase1和ATase2），并揭示了内质网生物学的一个新领域。具体来说，我们发现内质网乙酰化机制调节分泌途径内的蛋白质稳态以及不同细胞器和室间的代谢串扰。基于人类的研究发现，由纯合子和杂合子突变或基因重复事件导致的功能失调的内质网乙酰化与不同的人类疾病有关，从大脑发育迟缓和过早死亡到周围形式的神经病变、自闭症谱系障碍、智力残疾和节段性早衰。模拟这些遗传事件的小鼠模型概括了相关的人类疾病。重要的是，恢复内质网蛋白抑制功能的atase靶向化合物挽救了动物的疾病表型。