Ulk1-KO Mouse

Ulk1, short for unc-51 like autophagy activating kinase 1, is a serine/threonine kinase. It has an evolutionarily conserved role in the autophagy pathway. Ulk1 integrates signals from upstream energy sensors such as mTOR and AMPK and relays them to downstream autophagy machinery components. It is also involved in selective autophagy, removing damaged mitochondria, invading pathogens, and toxic protein aggregates. Alterations in its expression and activity are linked to pathophysiological processes like cancer, neurological, and cardiovascular diseases [3].

In breast cancer, ULK1 deficiency under hypoxia induces an invasive phenotype and increases osteolytic bone metastasis. Mechanistically, ULK1 depletion attenuates mitophagy, leading to damaged mitochondria, NLRP3 inflammasome activation, abnormal cytokine secretion, osteoclast differentiation, and ultimately bone metastasis [1]. In diabetic nephropathy, ULK1 is a potential biomarker. It may influence the disease development by regulating mitophagy. Its expression shows differences in glomeruli compared to tubulointerstitium, and it has correlations with immune cell infiltration and GFR [2]. In pancreatic β cells, DRAK2 phosphorylates ULK1 at Ser56, inducing its ubiquitylation and suppressing autophagy, which impairs β cell function during overnutrition [4].

In summary, Ulk1 is crucial for autophagy and selective autophagy processes. Gene knockout-related studies in models like breast cancer, diabetic nephropathy, and pancreatic β-cell function have revealed its significance in disease-associated biological processes. Understanding Ulk1's function through these models provides insights into potential therapeutic targets for related diseases.

References:

1. Deng, Rong, Zhang, Hai-Liang, Huang, Jun-Hao, Tang, Jun, Zhu, Xiao-Feng. 2020. MAPK1/3 kinase-dependent ULK1 degradation attenuates mitophagy and promotes breast cancer bone metastasis. In Autophagy, 17, 3011-3029. doi:10.1080/15548627.2020.1850609. https://pubmed.ncbi.nlm.nih.gov/33213267/

2. Yang, Yuan-Yuan, Gao, Zhong-Xiuzi, Mao, Zi-Hui, Liu, Zhang-Suo, Wu, Peng. 2023. Identification of ULK1 as a novel mitophagy-related gene in diabetic nephropathy. In Frontiers in endocrinology, 13, 1079465. doi:10.3389/fendo.2022.1079465. https://pubmed.ncbi.nlm.nih.gov/36743936/

3. Pareek, Gautam, Kundu, Mondira. 2024. Physiological functions of ULK1/2. In Journal of molecular biology, 436, 168472. doi:10.1016/j.jmb.2024.168472. https://pubmed.ncbi.nlm.nih.gov/38311233/

4. Lu, Yuting, Xu, Junyu, Li, Yufeng, Tan, Minjia, Li, Jingya. 2024. DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser56 to diminish pancreatic β cell function upon overnutrition. In Science translational medicine, 16, eade8647. doi:10.1126/scitranslmed.ade8647. https://pubmed.ncbi.nlm.nih.gov/38324636/