Researchers at St. Jude Children's Research Hospital have uncovered how two enzymes, ULK1 and ULK2, which are best known for their role in the degradation and recycling of proteins, control the trafficking of specific proteins. The control of the movement of these molecules from the endoplasmic reticulum (ER) to the Golgi apparatus is essential for maintaining the correct balance of cellular processes. The results are described online in the journal Molecular Cell and in time may help researchers understand how certain neurodegenerative diseases arise.
"Our results show that the involvement of ULK1 and ULK2 in ER-to-Golgi trafficking is essential for cellular homeostasis and protecting the well-being of the cell," said corresponding author Mondira Kundu, M.D., Ph.D., associate member of the St. Jude Department of Pathology. "Under typical physiological conditions, the role of ULK1 and ULK2 in trafficking of proteins is more important than its role in autophagy, at least in brain cells."
Autophagy maintains cellular homeostasis by recycling intermediate metabolites sequestered within double-membrane-bound vesicles, like phagosomes. The ER serves as a platform and a source of membranes for this process. Although the researchers were expecting autophagy to be defective when both enzymes were impaired, they were surprised stress arose in the ER that resulted in selective loss of neurons in the brains of mice (hippocampal neurons). Restoring ER-to-Golgi trafficking in cells deficient in the two enzymes quelled the ER stress response.
Mice engineered to lack the ULK 1 and 2 enzymes in the central nervous system showed a loss of neurons in the brain. Neuronal death was linked to the activation of the unfolded protein response, a cellular stress response that takes place in the ER. By looking at the proteins involved in this response the researchers were able to identify a key partner protein involved in the process. They also determined that phosphorylation of this protein was an important control point in the trafficking process that delivers proteins to the cell surface. The unexpected roles for ULK1 and ULK2 in promoting ER-to-Golgi trafficking of proteins, which seem to have been conserved throughout evolution, appear to be essential for maintaining cellular homeostasis and the integrity of the cell.
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The other authors are Joung Hyuck Joo, Rekha Iyengar, XiuJie Li-Harms, Christopher Wright, Timothy I. Shaw, Douglas R. Green, Junmin Peng, Linda M. Hendershot of St. Jude; Bo Wang of St. Jude and University of Tennessee Health Science Center; Elisa Frankel, Anjon Audhya of University of Wisconsin; Lu Xu, Ji Ying Sze of Albert Einstein College of Medicine; Liang Ge of University of California, Berkeley; Tullia Lindsten of Memorial Sloan Kettering Cancer Center; Fusun Kilic of University of Arkansas for Medical Sciences.
This research was supported by grants from the National Heart, Lung, and Blood Institute (R01 HL114697; R01 HL091196), the National Institute of Child Health and Human Development (R01 HD058697; R01 HD053477), the National Institute of General Medical Sciences (R01 GM110567; K99 GM114397), the National Institute of Aging (AG047928), the National Institute of Mental Health (MH105389); the Burroughs Welcome Fund (1006062.05); the American Society of Hematology; the American Heart Association (GRNT17240014); and ALSAC.
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Journal
Molecular Cell