Alternative titles; symbols
HGNC Approved Gene Symbol: ULK1
Cytogenetic location: 12q24.33 Genomic coordinates (GRCh38): 12:131,894,622-131,923,150 (from NCBI)
The C. elegans unc51 gene encodes a serine/threonine kinase expressed almost exclusively in neurons. Mutations in unc51 result in abnormal axonal extension and growth, leading to a paralyzed, egg laying-defective, and dumpy phenotype. By PCR with degenerate primers corresponding to subdomains of the unc51 catalytic domain, Kuroyanagi et al. (1998) isolated a rat neonatal brain cDNA showing significant homology to unc51. Using the rat fragment as a probe for screening human fetal brain and neuroblastoma NT-2 cDNA libraries, the authors cloned UNC51-like kinase-1 (ULK1) cDNAs. The predicted 1,050-amino acid human protein shares 29% sequence identity with nematode unc51. Northern blot analysis revealed that ULK1 was expressed as a 6-kb mRNA in all human adult tissues examined, with the highest levels in skeletal muscle and heart.
Chan et al. (2009) showed that the deduced 1,051-amino acid murine Ulk1 protein has an N-terminal kinase domain, followed by a long serine- and proline-rich spacer region and a C-terminal functional domain.
Using yeast 2-hybrid assays, Tomoda et al. (2004) determined that the C terminus of mouse Unc51.1 binds the C terminus of SynGAP (603384), a negative regulator of Ras (190020). Both Unc51.1 and SynGAP localized to the membrane fraction of mouse cerebral cortex lysates. Using a reporter assay, Tomoda et al. (2004) found that Unc51.1 inhibited SynGAP through its kinase activity. They provided evidence that Unc51.1 and SynGAP function cooperatively in axon formation.
Chan et al. (2009) found that murine Ulk1 and Ulk2 (608650) associated with different large molecular mass complexes. Mutation analysis showed that both kinase activity and the C-terminal domain of Ulk1 regulated its association with these complexes. Independent motifs within the C-terminal domains of Ulk1 and Ulk2 regulated autophosphorylation, membrane association, and binding and phosphorylation of human ATG13 (615088), an autophagosome protein. The isolated C-terminal domains of Ulk1 and Ulk2 functioned as dominant-negative inhibitors of starvation-induced autophagosome formation and protein degradation. Kinase-inactivated forms of Ulk1 and Ulk2 in HEK293 cells inhibited starvation-induced autophagy. Ulk1 associated with lipid raft markers in detergent-resistant membranes, and its membrane association was not altered following amino acid starvation. In contrast, Ulk2 became partially dephosphorylated and more strongly associated with autophagosomal membranes following amino acid starvation.
In a screen for conserved substrates of AMPK, Egan et al. (2011) identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic analysis of AMPK or ULK1 in mammalian liver and C. elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 results in aberrant accumulation of the autophagy adaptor p62 (601530) and defective mitophagy. Reconstitution of ULK1-deficient cells with a mutant ULK1 that cannot be phosphorylated by AMPK revealed that such phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. Egan et al. (2011) concluded that their findings uncovered a conserved biochemical mechanism coupling nutrient status with autophagy and cell survival.
Lin et al. (2012) reported that glycogen synthase kinase-3 (GSK3; 606784), when deinhibited by default in cells deprived of growth factors, activates acetyltransferase TIP60 (601409) through phosphorylating TIP60 serine at codon 86. This directly acetylates and stimulates the protein kinase ULK1, which is required for autophagy. Cells engineered to express TIP60(S86A) that cannot be phosphorylated by GSK3 could not undergo serum deprivation-induced autophagy. An acetylation-defective mutant of ULK1 failed to rescue autophagy in Ulk-null mouse embryonic fibroblasts. Cells used signaling from GSK3 to TIP60 and ULK1 to regulate autophagy when deprived of serum but not glucose. Lin et al. (2012) concluded that their findings uncovered an activating pathway that integrates protein phosphorylation and acetylation to connect growth factor deprivation to autophagy.
Yoon et al. (2020) provided evidence for a role of leucyl-tRNA synthetase-1 (LARS1; 151350) in glucose-dependent control of leucine usage. Upon glucose starvation, LARS1 was phosphorylated by ULK1 at the residues crucial for leucine binding. Phosphorylated LARS1 showed decreased leucine binding, which the authors proposed may inhibit protein synthesis and help save energy. Leucine that is not used for anabolic processes may be available for catabolic pathway energy generation. Yoon et al. (2020) concluded that the LARS1-mediated changes in leucine utilization might help support cell survival under glucose deprivation, and thus, depending on glucose availability, LARS1 may help regulate whether leucine is used for protein synthesis or energy production.
Southern blot analysis by Kuroyanagi et al. (1998) indicated that the ULK1 gene spans 30 to 40 kb.
By analysis of somatic cell hybrids and radiation hybrids, and by fluorescence in situ hybridization, Kuroyanagi et al. (1998) mapped the ULK1 gene to 12q24.3.
Associations Pending Confirmation
Among 569 individuals who self-identified as Asian or Black and had close contact with patients with tuberculosis, Horne et al. (2016) found that 273 (48%) developed latent Mycobacterium tuberculosis infection (LTBI) (see 607948). Genotyping of the ULK1 gene in 143 close contacts with LTBI and 106 close contacts without LTBI resulted in the identification of 2 SNPs in high linkage disequilibrium that were significantly associated with LTBI: rs12297124 and rs7300908. Further studies focused only on the G-to-T intronic transversion (rs12297124). A multivariable analysis showed that the minor allele of this SNP was associated with significantly reduced risk of LTBI (odds ratio of 0.32). In vitro studies of ULK1-deficient cells showed decreased TNF secretion after stimulation with Toll-like receptors and M. tuberculosis, increased M. tuberculosis replication, and decreased selective autophagy compared to controls. The findings suggested that variation in the ULK1 gene may affect susceptibility to the development of LTBI, possibly by affecting autophagy.
Kundu et al. (2008) found that Ulk1-null mice were viable and showed no overt developmental defects. However, they had mild splenomegaly, and the number and size of reticulocytes were increased compared with wildtype animals. Electron microscopy revealed a population of Ulk1-null red blood cells that retained mitochondria and ribosomes, which are usually eliminated by autophagy in the final stages of erythroid maturation. The defect in clearing mitochondria could be overcome by culturing Ulk1-null reticulocytes in the presence of a mitochondrial uncoupling agent. Ulk1-deficient mouse embryonic fibroblasts also showed an increase in mitochondrial mass. Autophagy could be induced in Ulk1-deficient fibroblasts by nutrient withdrawal. Kundu et al. (2008) concluded that ULK1 plays a general role in regulating mitochondrial clearance and is not critical for autophagy.
Chan, E. Y. W., Longatti, A., McKnight, N. C., Tooze, S. A. Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Molec. Cell. Biol. 29: 157-171, 2009. [PubMed: 18936157] [Full Text: https://doi.org/10.1128/MCB.01082-08]
Egan, D. F., Shackelford, D. B., Mihaylova, M. M., Gelino, S., Kohnz, R. A., Mair, W., Vasquez, D. S., Joshi, A., Gwinn, D. M., Taylor, R., Asara, J. M., Fitzpatrick, J., Dillin, A., Viollet, B., Kundu, M., Hansen, M., Shaw, R. J. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331: 456-461, 2011. [PubMed: 21205641] [Full Text: https://doi.org/10.1126/science.1196371]
Horne, D. J., Graustein, A. D., Shah, J. A., Peterson, G., Savlov, M., Steele, S., Narita, M., Hawn, T. R. Human ULK1 variation and susceptibility to Mycobacterium tuberculosis infection. J. Infect. Dis. 214: 1260-1267, 2016. [PubMed: 27485354] [Full Text: https://doi.org/10.1093/infdis/jiw347]
Kundu, M., Lindsten, T., Yang, C.-Y., Wu, J., Zhao, F., Zhang, J., Selak, M. A., Ney, P. A., Thompson, C. B. Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood 112: 1493-1502, 2008. [PubMed: 18539900] [Full Text: https://doi.org/10.1182/blood-2008-02-137398]
Kuroyanagi, H., Yan, J., Seki, N., Yamanouchi, Y., Suzuki, Y., Takano, T., Muramatsu, M., Shirasawa, T. Human ULK1, a novel serine/threonine kinase related to UNC-51 kinase of Caenorhabditis elegans: cDNA cloning, expression, and chromosomal assignment. Genomics 51: 76-85, 1998. [PubMed: 9693035] [Full Text: https://doi.org/10.1006/geno.1998.5340]
Lin, S.-Y., Li, T. Y., Liu, Q., Zhang, C., Li, X., Chen, Y., Zhang, S.-M., Lian, G., Liu, Q., Ruan, K., Wang, Z., Zhang, C.-S., Chien, K.-Y., Wu, J., Li, Q., Han, J., Lin, S.-C. GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science 336: 477-481, 2012. Note: Erratum: Science 337: 799 only, 2012. [PubMed: 22539723] [Full Text: https://doi.org/10.1126/science.1217032]
Tomoda, T., Kim, J. H., Zhan, C., Hatten, M. E. Role of Unc51.1 and its binding partners in CNS axon outgrowth. Genes Dev. 18: 541-558, 2004. [PubMed: 15014045] [Full Text: https://doi.org/10.1101/gad.1151204]
Yoon, I., Nam, M., Kim, H. K., Moon, H.-S., Kim, S., Jang, J., Song, J. A., Jeong, S. J., Kim, S. B., Cho, S., Kim, Y., Lee, J., and 12 others. Glucose-dependent control of leucine metabolism by leucyl-tRNA synthetase 1. Science 367: 205-210, 2020. [PubMed: 31780625] [Full Text: https://doi.org/10.1126/science.aau2753]