Stress Granules: The Cell's Secret First Responders

Imagine if your cells had an emergency team ready to spring into action when disaster strikes. Analogous to this, tiny stress-inducible structures called stress granules protect your cells when life throws unexpected challenges such as extreme heat, toxins, or even a viral infection. But here's the twist: these microscopic responders might also hold the key to treating some of humanity's most challenging diseases. The idea that cells have an "emergency response team" fascinated me from the moment I learned about it. I remember wondering if these tiny structures could hold secrets to combating diseases we struggle to treat.

In the Buchan lab, I explore the function and dynamics of stress granules and the ways they influence cell survival and human health.

Imagine your cells as bustling construction sites, tirelessly building proteins for various cellular processes around the clock using an incredible amount of energy. But what happens when cells find themselves in a suddenly stressful environment? To survive, the cell can't just keep building proteins as if nothing happened. It must adapt, prioritize cellular energy and resources, and even "pause" certain projects. That's where stress granules come in—they're like an emergency response team for your cells, helping cells hit pause on the synthesis of non-essential proteins and safeguarding critical resources such as mRNAs (the templates of protein synthesis) until the crisis is over. In the lab, I’ve seen just how resilient cells can be under stress. Observing how they "pause" non-essential functions and focus on survival inspired me to understand how we might harness this response for health benefits.

Stress granules are a type of liquid-like structure called biomolecular condensates. If that sounds complex, think of them like oil droplets in water—separate from their surroundings but able to merge, break apart, and exchange contents as needed.

How do stress granules form? It all starts with the cell's "alarm system"—the integrated stress response. When stress signals are detected, the cell activates enzymes called kinases that modify a protein called eIF2A, a critical player in protein synthesis. This modification acts like an emergency stop button, halting protein production temporarily allowing various proteins and mRNAs to be recruited into stress granules. I remember the first time I saw a time-lapse of stress granule formation in our lab—it was like watching the cell’s defense system come to life in real-time. It gave me a sense of awe at how quickly and precisely cells can react to stress. Rather than letting mRNAs get damaged or maybe even misused during all the chaos, the cell tucks them away in stress granules for safekeeping until it's time to "unpause" the construction projects and get back to work.

When the crisis subsides, the cell begins dismantling stress granules to resume normal protein production. The cells can't just have their protein production sites on pause forever—they need the resources to recover, which includes rebuilding and repairing damages caused by stressors. During stress granule clearance, specialized cellular machinery steps in to carefully extract mRNAs and dissolve stress granules to get various protein-building projects back on track. This stage of dismantling stress granules intrigues me the most because it’s where we see the transition back to normalcy. It feels like watching a city rebuild after a storm—a process I hope we can better understand to help treat diseases where this phase fails.

Now, why does all this matter? Zooming out, stress granules play significant roles in diseases like cancer, viral infections, and neurodegenerative disorders such as Amyotrophic lateral sclerosis (ALS – often called Lou Gehrig’s disease). It is thought that ineffective clearance of stress granules can cause problems. Imagine a construction site where materials are piling up everywhere—disorganization like this can lead to serious issues. In ALS, a stress granule-localizing protein called TDP-43 misbehaves by forming clumps or aggregations within cells—a process that may be facilitated by extended localization in stress granules. This disrupts normal cellular functions and contributes to the symptoms of ALS and similar disorders.

Understanding this has deepened my commitment to finding answers. Knowing that stress granules may contribute to diseases like ALS and cancer drives me to work toward solutions that could one day make a real impact. I am interested in understanding how stress granules normally limit hazardous pileups of potentially toxic materials like misfolded TDP-43 or redirect resources (mRNA and proteins) as needed during stress recovery. This knowledge could eventually lead to treatments for diseases where chronic stress and stress granules play a critical role.

Story written by Mohammed Ahmed Jalloh, a second year MCB PhD student working in the Buchan Lab.