Institute of Environmental MedicineToxicology Unit, Karolinska Institutet, Stockholm Sweden.
Division of Biochemistry, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
Autophagy. 2022 Dec;18(12):2769-2780. doi: 10.1080/15548627.2022.2039993. Epub 2022 Feb 28.
Macroautophagy/autophagy is a tightly regulated catabolic process, which contributes at baseline level to cellular homeostasis, and upon its stimulation to the adaptive cellular response to intra- and extracellular stress stimuli. Decrease of autophagy activity is occurring upon aging and thought to contribute to age-related-diseases. Recently, we uncovered, upon autophagy induction, the role of DNMT3A (DNA methyltransferase 3 alpha)-mediated DNA methylation on expression of the MAP1LC3 (microtubule associated protein 1 light chain 3) proteins, core components of the autophagy pathway, which resulted in reduced baseline autophagy activity. Here, we report that serine/threonine kinase ULK3 (unc-51 like kinase 3)-dependent activation of GLI1 (GLI family zinc finger 1) contributes to the transcriptional upregulation of gene expression upon autophagy induction, thereby bringing additional understanding of the long-term effect of autophagy induction and a possible mechanism for its decline upon aging, pathological conditions, or in response to treatment interventions. CBZ: carbamazepine; ChIP: chromatin immunoprecipitation; Clon: clonidine; DNMT3A: DNA methyltransferase 3 alpha; GLI1: GLI family zinc finger 1; GLI2: GLI family zinc finger 2; MAP1LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; PLA: proximity ligation assay; RT-qPCR: quantitative reverse transcription PCR; shRNA: small hairpin RNA; siRNA: small interfering RNA; Treh: trehalose; ULK3: unc-51 like kinase 3.
自噬是一种严格调控的分解代谢过程，它在基础水平上有助于细胞内稳态，并且在受到刺激时有助于细胞对内、外应激刺激的适应性反应。自噬活性的降低发生在衰老过程中，被认为与与年龄相关的疾病有关。最近，我们发现，在自噬诱导时，DNMT3A（DNA 甲基转移酶 3α）介导的 DNA 甲基化对自噬途径的核心组成部分 MAP1LC3（微管相关蛋白 1 轻链 3）蛋白的表达有影响，导致基础自噬活性降低。在这里，我们报告说丝氨酸/苏氨酸激酶 ULK3（UNC-51 样激酶 3）依赖性的 GLI1（GLI 家族锌指蛋白 1）的激活有助于自噬诱导时基因表达的转录上调，从而进一步了解自噬诱导的长期影响及其在衰老、病理条件下或对治疗干预的反应中下降的可能机制。CBZ：卡马西平；ChIP：染色质免疫沉淀；Clon：可乐定；DNMT3A：DNA 甲基转移酶 3α；GLI1：GLI 家族锌指蛋白 1；GLI2：GLI 家族锌指蛋白 2；MAP1LC3：微管相关蛋白 1 轻链 3；MTOR：雷帕霉素靶蛋白激酶；PLA：邻近连接分析；RT-qPCR：定量逆转录 PCR；shRNA：短发夹 RNA；siRNA：小干扰 RNA；Treh：海藻糖；ULK3：UNC-51 样激酶 3。
