The Role of TXNIP in Amino Acid Management
TXNIP regulates amino acid transport, influencing cell growth and quiescence.
Jennifer Kahlhofer, Nikolas Marchet, Brigitta Seifert, Kristian Zubak, Madlen Hotze, Anna-Sophia Egger, Claudia Manzl, Yannick Weyer, Sabine Weys, Martin Offterdinger, Sebastian Herzog, Veronika Reiterer, Marcel Kwiatkowski, Saskia B. Wortmann, Siamak Nemati, Johannes A. Mayr, Johannes Zschocke, Bernhard Radlinger, Kathrin Thedieck, Lukas A. Huber, Hesso Farhan, Mariana E.G. de Araujo, Susanne Kaser, Sabine Scholl- Bürgi, Daniela Karall, David Teis
― 7 min read
Table of Contents
- Transporting Amino Acids
- Cellular Growth and Amino Acids
- The Mystery of Quiescent Cells
- The Role of Txnip
- TXNIP and Endocytosis
- Observing the Changes
- What Happens in Starvation
- TXNIP’s Role in Starvation
- Findings with TXNIP Deficiency
- Experimenting with Cell Models
- Analyzing Cell Behavior
- Visualizing Transporters
- Transporter Dynamics
- Understanding TXNIP Function
- Examining TXNIP Mutations
- TXNIP’s Influence on Cell Growth
- The Cell Cycle Connection
- The Bigger Picture
- Conclusion: Bringing it All Together
- Original Source
- Reference Links
Amino Acids are the building blocks of proteins, and they play a crucial role in everything from muscle building to hormone production. Our bodies have 20 essential proteinogenic amino acids that we need to survive. Cells have to carefully manage these amino acids, making sure they have enough for their needs without going overboard, sort of like how you manage your snack intake during movie night-too few and you’re starving, too many and you’re rolling off the couch!
Transporting Amino Acids
To keep the right balance of amino acids, cells use special proteins called Transporters. In humans, there are at least 66 of these transporters, which belong to different families. Think of these transporters as the delivery trucks of amino acids, bringing the good stuff into the cell and taking out the trash when necessary. If something goes wrong with these transporters, it can lead to diseases, just like a broken delivery truck could ruin a good pizza night.
Cellular Growth and Amino Acids
When cells are busy dividing and growing, they need more amino acids. This is especially true for cancer cells, which go into overdrive. They bump up the number of transporters on their surface to soak up all the amino acids like a sponge. But when cells take a break from growing-known as quiescence-they have to dial back on the amino acid intake. It’s like switching from a buffet to a snack-size plate when you’re not that hungry anymore.
Quiescent Cells
The Mystery ofIn a resting state, cells shrink a bit and slow down their activity. They need to find a way to take in fewer amino acids, but how they do this is still a bit of a mystery. It’s like trying to figure out how to keep your fridge stocked with just the right amount of food when you’re on a diet.
Txnip
The Role ofHere’s where TXNIP comes into play. TXNIP is like the manager of the amino acid transporters. It helps remove these transporters from the cell's surface when cells enter the quiescent state. This means there are fewer delivery trucks on the road, leading to less amino acid being taken in.
In simpler terms, TXNIP is like a bouncer at a club, ensuring that only the right amount of guests (amino acids) get in when the party (cell growth) is winding down.
TXNIP and Endocytosis
TXNIP operates through a process called endocytosis, where the cell wraps around the transporters and pulls them inside. This process requires a little help from specific proteins. It’s a bit like taking down decorations after a party-you need the right tools to get everything off the walls.
Observing the Changes
Researchers have found that when cells are starved of serum but have amino acids available, they begin to change. The amount of certain amino acid transporters decreases, indicating that cells are indeed adjusting to their quiescent state. This behavior is similar in various cell types, reinforcing the idea that TXNIP plays a central role across different cellular systems.
What Happens in Starvation
When cells go without serum for a while, they shrink in size and reduce their activity. In studies, scientists noticed decreased levels of specific transporters at the cell surface. It’s like when you decide to clean out your closet and end up getting rid of clothes you haven’t worn in ages.
TXNIP’s Role in Starvation
During serum starvation, TXNIP levels actually go up. This increase signals the need to remove amino acid transporters, showing the cell is turning down the intake. Imagine a factory reducing its workforce during a slow period-it keeps only what's necessary to keep operating.
Findings with TXNIP Deficiency
Scientists discovered that without TXNIP, cells can’t effectively remove transporters. This ultimately leads to too many amino acids piling up inside the cell, much like hoarding items that don’t get used.
In a patient with a rare mutation leading to TXNIP deficiency, researchers found that the regulation of amino acids was thrown off balance, resulting in various health problems. It’s like trying to make a cake without measuring the ingredients properly-the results can be messy!
Experimenting with Cell Models
To understand amino acid transport better, scientists used a type of human retinal pigment epithelial cells. They treated these cells with serum and then starved them of serum to watch how they adapted. By analyzing their growth phases, they could see how well the cells managed amino acid intake.
Analyzing Cell Behavior
Through various tests, the scientists checked how well the amino acid transporters were working. They found that certain transporters decreased in number during quiescence, while others stayed constant. This highlighted how the cells were adjusting based on their environment.
Visualizing Transporters
With advanced imaging techniques, researchers could see the transporters on the cell surface. They noted that when cells were starved, these transporters were effectively removed from the surface, further affirming TXNIP’s role in regulating this process.
Transporter Dynamics
They even treated cells with substances that blocked the recycling process, demonstrating the necessity of endocytosis for removing transporters. The results showed that when the normal recycling process was disrupted, the transporters stuck around longer than they should have, like guests overstaying their welcome at a party.
Understanding TXNIP Function
Researchers also looked into how TXNIP interacts with other proteins that control the endocytosis process. They found that TXNIP uses special regions to bind to the endocytic machinery, emphasizing its importance in regulating amino acid transport.
Examining TXNIP Mutations
In patients with TXNIP mutations, the effects on transporters became even clearer. Patient-derived cells showed that without functional TXNIP, transporters didn’t get removed from the surface like they should. This led to various issues with amino acid balance, showing the importance of proper TXNIP function for cellular health.
TXNIP’s Influence on Cell Growth
The findings also indicated that TXNIP’s role went beyond just managing amino acids; it also influenced overall cell growth. Cells with TXNIP deficiencies tended to grow faster, similar to kids who skip their veggies and jump straight to dessert-great in the short term but not the best for long-term health.
The Cell Cycle Connection
As cells transitioned between growth phases, scientists noticed TXNIP’s influence on the cell cycle. Cells that could not properly downregulate transporter levels were more likely to move quickly through the cell cycle, illustrating how nutrients impact growth.
The Bigger Picture
The implications of this research are significant, not just for understanding cell biology but also for human health. By grasping how TXNIP functions in regulating amino acid transport, we can better understand metabolic diseases linked to amino acid imbalances.
Conclusion: Bringing it All Together
In summary, TXNIP plays a vital role in controlling how cells manage amino acids, especially during times of growth and quiescence. It ensures that cells don’t overload on amino acids when they don’t need them, keeping everything in balance. Much like life, it’s all about finding the right proportions-too much of a good thing can lead to chaos.
Through studying TXNIP, researchers not only uncover the nuances of cellular behavior but also potential pathways for addressing metabolic disorders in humans. So next time you think about amino acids, remember the essential roles they play and how cells manage their intake with the help of trusty TXNIP!
Title: TXNIP mediates LAT1/SLC7A5 endocytosis to reduce amino acid uptake in cells entering quiescence
Abstract: Entry and exit from cellular quiescence require dynamic adjustments in nutrient acquisition, yet the mechanisms by which quiescent cells downregulate amino acid (AA) transport remain poorly understood. Here, we demonstrate that cells entering quiescence select plasma membrane-resident AA transporters for endocytosis and lysosomal degradation, to match AA uptake with reduced translation. We identify the -arrestin TXNIP as a key regulator of AA uptake during quiescence, since it mediates the endocytosis of the SLC7A5-SLC3A2 (LAT1-4F2hc) transporter complex in response to reduced AKT signaling. Mechanistically, TXNIP interacts with HECT-type ubiquitin ligases to facilitate transporter ubiquitination. Loss of TXNIP disrupts this regulation, resulting in dysregulated AA uptake, sustained mTORC1 signaling, and accelerated quiescence exit. A novel TXNIP loss-of-function mutation in a patient with severe metabolic disease further supports its role in nutrient homeostasis and human health. These findings highlight TXNIPs role in controlling SLC7A5-SLC3A2 mediated AA acquisition with implications for quiescence biology and disease.
Authors: Jennifer Kahlhofer, Nikolas Marchet, Brigitta Seifert, Kristian Zubak, Madlen Hotze, Anna-Sophia Egger, Claudia Manzl, Yannick Weyer, Sabine Weys, Martin Offterdinger, Sebastian Herzog, Veronika Reiterer, Marcel Kwiatkowski, Saskia B. Wortmann, Siamak Nemati, Johannes A. Mayr, Johannes Zschocke, Bernhard Radlinger, Kathrin Thedieck, Lukas A. Huber, Hesso Farhan, Mariana E.G. de Araujo, Susanne Kaser, Sabine Scholl- Bürgi, Daniela Karall, David Teis
Last Update: 2024-12-04 00:00:00
Language: English
Source URL: https://www.biorxiv.org/content/10.1101/2024.10.29.620655
Source PDF: https://www.biorxiv.org/content/10.1101/2024.10.29.620655.full.pdf
Licence: https://creativecommons.org/licenses/by/4.0/
Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.
Thank you to biorxiv for use of its open access interoperability.