ULK1 and ULK2 are ubiquitously expressed protein kinases localized to autophagosomal membranes in mammalian cells. The ability of dominant negative mutants of ULK1 and ULK2 to block autophagy led to the hypothesis that ULK1 and ULK2 are redundant protein kinases.
An overview of ULK
Mammals have two yeast autophages to initiate ATG1 kinase homologous proteins, including ULK1 and ULK2. There is growing evidence that ULK1 protein kinase is an important regulatory factor for autophagy initiation and progression. ULK1 is also a serotonin/tributyl kinase that is critical for the initial stage of autophagy. When the amino acid is lacked or mTOR is inhibited, the activated ULK1 will phosphorylate ser 14 point of Beclin-1, thereby increasing VPS34 complex activity. It is necessary for mammals to induce autophagy by ULK, which leads to Beclin-1 Ser 14 point phosphorylated, and it is conserved in the caenorhabditis elegans.
Inhibition of ULK
MRT68921 hydrochloride is an inhibitor with the most effective ULK1 and ULK2. MRT68921 can inhibit ULK1 and ULK2 in test tubes and prevents autophagy. The self-inhibition ability of this compound is achieved by ULK1. And the accumulation of stalled early autophagosomal structures is resulted due to the inhibition of ULK1, indicating the role of ULK1 in the maturation and initiation of autophagosomes.
ULK and diseases
By knocking out the Atg5 and Atg7 genes in the brain of mice, it was found that a large number of neurons in the brain had died and the accumulation of ubiquitin inclusion bodies increased. The common pathological features of most neurodegenerative diseases are the presence of easily aggregated proteins in the neurons, such as the mutant alpha-synapse protein (α-synuclein), amyloid precursor protein, tau protein, and huntingtin protein. They have toxic effects on neurons that eventually lead to the death of neurons, and the corresponding clinical symptom appears. Studies have shown that mutations in easily aggregated proteins are mainly cleared by autophagy. The death of neurons is irreversible, so it is important for these diseases to remove or degrade the abnormal aggregation of the cells by autophagy. ULK is a complex composed of Atg1, Atg11, Atg13, Atg17, Atg29, and Atg31. Under the condition of nutrient deficiency, yeast Atg17, Atg29, and Atg31 form a complex, and Atg13 and Atg17 bind to activated Atg1 kinase. Then ATGL and ATGL3 interact to regulate the formation of the anterior autophagy.