A recent study explains how cells that lack nutrients redirect protein transport stations to cellular recycling centers, where they are broken down. This reveals a unique method that cells use to cope with challenging conditions.
A new study explains how cells that lack nutrients redirect protein transport stations to cellular recycling centers, where they are broken down. This reveals a unique method that cells use to cope with challenging conditions.
New proteins bound for outside the cell are manufactured on the endoplasmic reticulum (ER) — a snaking membrane inside the cell. Grape-like tubular outgrowths on the ER called ERThe ER exit sites act as hubs for transporting newly synthesized proteins to their next destination. In addition to their role in protein transport, scientists have found that these sites also help with the delivery of cellular material and misfolded proteins to lysosomes, which are responsible for breaking down and recycling cellular waste. Furthermore, the ER exit sites provide a platform for virus replication, including COVID-19. Researchers were initially puzzled by how this single structure could be involved in such diverse functions. However, a recent study conducted by researchers from HHMI’s Janelia Research Campus, led by Ya-Cheng Liao, aims to shed light on this mystery. Liao is a former postdoctoral researcher at Janelia.Research conducted by a former member of the Lippincott-Schwartz lab, who is now an assistant professor at Columbia University, used advanced imaging techniques to study the impact of nutrient stress on ER exit sites. The study revealed that when cells are under stress, a sequence of molecules collaborate to guide ER exit sites to lysosomes where they are broken down. This process represents a new pathway that cells may use to release amino acids required for protein synthesis. The researchers demonstrated how ER exit sites are transferred and consumed by specific lysosomes when cells experience nutrient deprivation. Furthermore, the team provided a detailed explanation of the molecular mechanisms involved in this process.The process begins with starving cells triggering the release of calcium from lysosomes, which then causes the recruitment of an enzyme called ALG2 to the ER exit sites where it binds to a structure known as COPII. This connection between ALG2 and COPII initiates a process called ubiquitination, which is responsible for protein degradation. The lysosome recognizes the ubiquitin produced by this process, leading the ER exit site to the lysosome for destruction of cellular material.
The process involves ALG2, which is connected to the ER exit site and binds to another protein, ALIX, once it reaches the lysosome. ALIX then interacts with ESCRT, a protein complex on the lysosome surface that is involved in ingestion. This interaction causes the ER exit site and the lysosome to move closer together, eventually leading to the engulfment and ingestion of the ER exit site by the lysosome.
In addition to observing this process in live cells, the team also recreated it in an artificial system to confirm how all the different components work together.
This new research uncovers a unique pathway that cells utilize to combat stress, providing valuable insight that could.This study aims to improve our understanding of the aging process in cells and organisms, as well as shed light on other processes related to ER exit sites. This includes how viruses are transported outside of cells through lysosomes, presenting a potential avenue for developing new treatments. The research findings are published in the journal “Developmental Cell.