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Defining how metabolites are transported across organelle membranes reveals fundamental principles of cell biology and disease. Credit: Neuroscience News<\/p>\nSummary: The endoplasmic reticulum (ER) is the cell\u2019s busiest manufacturing hub, responsible for folding and exporting proteins. For decades, scientists knew the ER required a very specific chemical balance to function, but the \u201cmachinery\u201d behind it was a mystery.<\/p>\n
Now, researchers have identified a protein called SLC33A1 that acts as a glutathione regulator. The study reveals that this regulator ensures proteins are folded correctly, a process that, when broken, leads to the toxic \u201cclogs\u201d found in neurodegenerative diseases and cancer.<\/p>\n
Key Findings<\/p>\n
Mitochondria vs. ER: While glutathione \u201ckeeps the lights on\u201d in the mitochondria, its primary job in the ER is \u201cquality control.\u201dFirst Visual Evidence: Working with Memorial Sloan Kettering, the team was able to visualize exactly how the SLC33A1 protein binds and moves its cargo across the ER membrane.New Therapeutic Avenues: Identifying this transporter opens the door for synthesis inhibitors that could treat neurodevelopmental disorders or specific types of cancer by manually recalibrating the cell\u2019s glutathione levels.<\/p>\n
Source: Rockefeller University<\/p>\n
In the past several years, Rockefeller University\u2019s\u00a0Kivan\u00e7 Birsoy\u00a0and his team in the Laboratory of Metabolic Regulation and Genetics have revealed remarkable details about the antioxidant glutathione, which plays many essential roles in the body, from clearing free radicals to repairing cellular damage. <\/p>\n
Among other things, they\u2019ve discovered the\u00a0transporter\u00a0that shuttles glutathione to where it\u2019s needed, how glutathione keeps iron levels in check, and the metabolite\u2019s complicated relationship with mitochondria, the energy center of the cell, where it both\u00a0keeps the lights on\u00a0yet can drive the\u00a0metastasis of breast cancer.<\/p>\n
Defining how metabolites are transported across organelle membranes reveals fundamental principles of cell biology and disease. Credit: Neuroscience News<\/p>\n
Now they\u2019ve discovered glutathione\u2019s key part in maintaining the smooth operations of a protein-producing hub in the cell called the endoplasmic reticulum (ER). They shared their results in a\u00a0paper\u00a0published in\u00a0Nature Cell Biology.<\/p>\n
\u201cRockefeller has an incredibly rich history of research on the endoplasmic reticulum, so we know that when things go wrong in this organelle, many diseases ranging from neurodegeneration to cancer can result,\u201d says Birsoy. \u201cWe discovered a glutathione regulator in the ER that likely plays a key role in these conditions.\u201d<\/p>\n
That regulator, they learned, acts as a crucial proofreader, ensuring proteins in the ER are folded correctly.<\/p>\n
Striking the right balance<\/p>\n
Birsoy\u2019s team discovered a few years ago that if glutathione levels aren\u2019t precisely maintained in mitochondria, all systems fail. Among those team members were co-first authors Shanshan Liu, a postdoc in the lab who has long researched mitochondrial metabolism, and Mark Gad, a Ph.D student jointly supervised by Birsoy and Richard Hite, of Memorial Sloan Kettering Cancer Center.<\/p>\n
On the heels of their initial findings, the group began to wonder about glutathione\u2019s impact in the ER, which works with the mitochondria to keep the cell in a state of homeostasis.<\/p>\n
Based on previous work, the team knew that glutathione contributes to maintaining the tightly regulated, Goldilocks-like environment of the ER, where secretory and membrane proteins manufactured by ribosomes are folded for export. These proteins are then exported into the cytosol (the jelly-like fluid that fills the cell) and then move further afield to complete their assigned tasks.<\/p>\n
Unlike in the mitochondria\u2014where the ratio between different forms of glutathione favors the unoxidized version\u2014the ER prefers an oxidized environment. So, working with Hite\u2019s lab, the team set out to discover not just why that is, but also what mechanisms calibrate the optimal ratio.<\/p>\n
Quality control<\/p>\n
After developing a new method to rapidly profile the chemical landscape within the ER, Liu began to directly observe functions within the organelle. She discovered that the ER maintains its oxidized equilibrium by importing from the cytosol an oxidized form of glutathione called GSSG and exporting a reduced form called GSH. The ER maintains its balance by keeping a high ratio of GSSG to GSH.<\/p>\n
A genetic screening revealed that a transporter called SLC33A1 oversees this process. Structural studies performed by Gad in collaboration with the Hite lab further confirmed that SLC33A1 protein indeed transports GSSG and revealed biochemical details of this process.<\/p>\n
\u201cBefore this work, we knew the ER needed to stay oxidized to fold proteins correctly, but the machinery responsible for maintaining that balance was essentially a black box,\u201d says Gad.<\/p>\n
\u201cWe discovered that the correct glutathione ratio is essential to a proofreading step in protein folding. It may even be its primary job,\u201d Liu says. \u201cSo if something goes wrong and the GSSG accumulates, it inhibits an enzyme that relies on the correct oxidation of the ER environment to operate a protein quality control system.\u201d<\/p>\n
Moreover, they discovered, when misfolded proteins don\u2019t pass quality control, they won\u2019t get exported, so they too pile up in the ER. Eventually this excess debris can lead to cell death.<\/p>\n
\u201cIdentifying SLC33A1 as the key exporter\u2014and being able to visualize exactly how it binds its cargo\u2014gives us a handle on a process that, when it goes wrong, is linked to neurodegeneration and cancer,\u201d says Gad.<\/p>\n
Neurodevelopmental disorders and cancer<\/p>\n
To that point, the researchers also identified glutathione-linked molecular mechanisms that may contribute to very different diseases. The first is Huppke-Brendel Syndrome, a severe neurodevelopmental disorder characterized by severe intellectual disability, motor deficits, and progressive neurodegeneration. Until now, researchers knew it was linked to mutations in the gene that produces the SLC33A1 transporter but little else.<\/p>\n
\u201cOur findings raise the possibility that the dysfunction of this gene alters the delicate glutathione balance in the ER and leads to protein misfolding during brain development,\u201d Liu says. \u201cWe think this could lead to new interventions, such as reducing the glutathione overload through synthesis inhibitors or compounds that can dissipate it.\u201d<\/p>\n
The findings also have implications for potential therapies for lung cancers related to mutations in the\u00a0KEAP1\u00a0gene.<\/p>\n
\u201cThese cancer cells rely on a high level of glutathione synthesis,\u201d she adds. \u201cSo if we were to inhibit the SLC33A1 transporter, the GSSG would accumulate, and the cancer cells would die.\u201d<\/p>\n
\u201cOur work demonstrates that defining how nutrients and metabolites are transported across cellular and organelle membranes reveals fundamental principles of cell biology while uncovering a major class of disease-relevant and therapeutically tractable proteins,\u201d Birsoy says. \u201cWe will continue to illuminate this largely uncharted area in future work.\u201d\u00a0\u00a0<\/p>\n
Key Questions Answered:Q: Why does it matter if a protein is \u201cmisfolded\u201d?<\/p>\n
A: A protein\u2019s shape determines its function. A misfolded protein is like a key with the wrong teeth, it won\u2019t open the door, and it gets stuck in the lock. When thousands of these \u201cstuck keys\u201d pile up in the ER, the cell eventually dies.<\/p>\n
Q: Could this lead to a treatment for Alzheimer\u2019s?<\/p>\n
A: While this study focused on Huppke-Brendel Syndrome, many neurodegenerative diseases (like Alzheimer\u2019s and Parkinson\u2019s) are characterized by misfolded proteins. Understanding how to fix the ER\u2019s \u201cproofreading\u201d system could eventually help us clear those toxic protein clumps.<\/p>\n
Q: How does this help fight cancer?<\/p>\n
A: Cancer cells are \u201caddicted\u201d to glutathione to survive their own rapid growth. By blocking the SLC33A1 transporter, we can disrupt their internal chemistry, causing an \u201coverload\u201d of oxidized glutathione that triggers the cancer cell to self-destruct.<\/p>\n
Editorial Notes:This article was edited by a Neuroscience News editor.Journal paper reviewed in full.Additional context added by our staff.About this genetics and neuroscience research news<\/p>\n
Author:\u00a0Katie Fenz<\/a>
Source:\u00a0Rockefeller University<\/a>
Contact:\u00a0Katie Fenz \u2013 Rockefeller University
Image:\u00a0The image is credited to Neuroscience News<\/p>\n