Akash Singh, Banaras Hindu University
Autophagy, often blamed for senescence, is a conserved process that promotes cellular homeostasis by degrading cytosolic components (sometimes referred to as cargo). This cargo sequestered into autophagosomes, which are double-membrane vesicles that are primarily carried in the retrograde direction to the perinuclear area, where they combine with lysosomes, ensuring cargo destruction. Hansen lab’s research that focuses on the relationship between ageing and autophagy has made the discovery of a potential entry point in the regulation of autophagosomes. This discovery opens up many prospects for investigating the declined autophagic functions in ageing cells.
Autophagy and ageing:
Autophagy is a key protein turnover mechanism that transports cellular components to lysosomes for destruction and recycling. Under stress, this intracellular activity is capable of maintaining cellular homeostasis, and its disruption could result in physiological changes. Autophagic activity has been reported to diminish with age, which may contribute to the accumulation of damaged macromolecules and organelles as people age.
Discovery of a potential entry point:
According to Jose Luis Nieto-Torres, a postdoc in the Hansen lab and the study’s first author, “Movement of these autophagosomes in a cell is like moving garbage trucks along a highway.” They studied the process in nerve cells since the nerve cells are long and flat. This nature of the cells allowed them to visualize the directional aspects of transport. These aspects help in recycling cellular waste via the process of autophagy.
The recent findings from Hansen’s lab shed light on the significance of phosphorylation of the protein LCB3, which aids in bidirectional autophagosome transport. The results, which were published in Current Biology, detail how autophagosomes are marked to direct their travel to waste-processing cellular “recycling plants”. They previously discovered that autophagy requires the tagging of LCB3, a protein present on the surface of autophagosomes. In their latest research, they describe how tagging occurs and how critical it is for autophagosome migration.
They revealed that the Hippo kinase STK4/MST1 initiated phosphorylation of Threonine-50 on the LC3B/ATG8 complex inhibits the binding of adaptor transport protein FYCO1 to the LCB3/ATG8 complex. FYCO 1 aids in the anterograde transport of autophagosomes to the cell periphery; hence, lowering FYCO1 binding results in a decrease in anterograde autophagosome transport. They also demonstrated that inhibiting LC3B phosphorylation reduced autophagosome retrograde transport, reducing the autophagosome-lysosome interaction. They conclude that the STK4-LC3B-FYCO1 axis is nutrient-sensitive and that post-translational modification of LC3B aids in the regulation of directional transport of autophagosomes, a vital stage in the autophagy process.
Future Prospects:
Now that scientists understand how phosphorylation influences autophagosome mobility, they can investigate the link between autophagy and age-related diseases like cancer and neurological problems. It will also assist in determining how waste products are chosen for recycling and how a cell chooses when to begin transferring waste.
Discovering the likely initial entrance site that controls recycling activity in cells would also help researchers better understand why autophagy functions decline as cells age, as well as lead to the development of new therapeutic targets and diagnostic markers to measure autophagy.
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References:
- Nieto-Torres, J. L., Shanahan, S. L., Chassefeyre, R., Chaiamarit, T., Zaretski, S., Landeras-Bueno, S., Verhelle, A., Encalada, S. E., & Hansen, M. (2021). LC3B phosphorylation regulates FYCO1 binding and directional transport of autophagosomes. Current biology : CB, S0960-9822(21)00750-8. Advance online publication. https://doi.org/10.1016/j.cub.2021.05.052
- Todde, V., Veenhuis, M., & van der Klei, I. J. (2009). Autophagy: principles and significance in health and disease. Biochimica et biophysica acta, 1792(1), 3–13. https://doi.org/10.1016/j.bbadis.2008.10.016
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About the author:
Akash Singh is a first-year master’s student of Biochemistry at Banaras Hindu University. He plans to pursue a Ph.D. in the future and also teach the young minds of the country. He is generally inclined to the field of scientific writing. Some of his writings are:
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