Scientists at Sanford Burnham Prebys have gained a deeper understanding of the intricacies of autophagy, the process by which cells break down and recycle parts of cells. The results, published in Current biology, describe how the “garbage bags” in a cell – called autophagosomes – are marked to direct their movement to the cellular “recycling facilities” that process waste. The research opens new avenues to understand the link between autophagy and age-related diseases such as cancer and neurological disorders.

“Our latest study shows how a chemical modification (phosphate-related tag) of an important autophagosome component, the protein called LCB3, helps direct the transport of autophagosomes within the cell in the right direction,” says Malene Hansen, Ph .D., Professor at Sanford Burnham Prebys and lead author on the study. “We previously reported that LCB3, which is on the surface of autophagosomes, needs to be labeled for autophagy to work effectively. Now we have a better understanding of how tagging works and how important it is for autophagosome movement. ”

In addition to their own laboratory studies, Hansen’s laboratory worked with colleagues in the laboratory of Sandra Encalada, Ph.D., at the Scripps Research Institute, San Diego, who are leaders in the transport of cellular components in neurons. These studies showed that blocking the chemical modification of the LC3B protein interfered with the efficient transport of autophagosomes to the cellular recycling facilities.

“Transporting waste in a cell is like driving garbage trucks on a freeway,” says Jose Luis Nieto-Torres, Ph.D., postdoc in the Hansen laboratory and lead author of the study. “Together with our staff, we examined the process in nerve cells because they are long and flat, which helps us to observe the directional aspects of transport, a critical aspect for waste recycling through autophagy.

“We clearly saw that autophagosomes or the garbage bags filled with rubbish did not move in the direction of the lysosomes, the cell recycling facility, if the phosphate labeling of LC3B was obstructed. This is potentially very harmful to a cell’s health. It’s kind of like what would happen if a garbage truck didn’t pick up your rubbish – your rubbish could build up, get scattered around the neighborhood and pose a health hazard. ”

As a next step, the researchers want to find out which waste products are selected for recycling and how a cell determines when it should start with the waste.

“My lab’s research efforts focus on the relationship between aging and autophagy,” concludes Hansen. “Based on this discovery, we have a new potential entry point to modulate recycling activity in a cell, which may prove relevant to understanding the decreased functions of autophagy that are known to occur in aging cells . Such findings could ultimately lead to new drug targets for combating age-related diseases as well as potential diagnostic markers for assessing the “health” of autophagy, an important goal for the future. ”

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Other study authors are Sean-Luc Shanahan and Sviatlana Zaretski from Sanford Burnham Prebys; and Romain Chassefeyre, Tai Chaiamarit, Sara Landeras-Bueno, Adriaan Verhelle, and Sandra E. Encalada of Scripps Research.

The DOI of the study is 10.1016 / j.cub.2021.05.052

The research reported in this news release was supported by funding from Jose L. Nieto-Torres through a Fundacion Ramon Areces postdoctoral fellowship and a K99 / R00 National Institutes of Health (NIH) Independence Path (K99AG062774); Romain Chassefeyre was supported by the George E. Hewitt Foundation for Medical Research; and Tai Chaiamarit was supported by a grant from the Royal Thai Government from the Scientific and Technological Talent Development and Promotion Project. This work was also funded by grants to Sandra E. Encalada: an NIH R01 AG049483 grant; the Glenn Foundation for Medical Research Glenn Award for research into biological mechanisms of aging; a New Scholar in Aging Award from the Lawrence Ellison Foundation; the Baxter Family Foundation; and to Malene Hansen, an NIH R01 GM117466 fellowship.

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