New research reveals how SNHG15, a molecule in our own cells, works with RABL2A to boost the virus's ability to enter cells.
Published: October 15, 2023
Imagine your body as a fortress, and each of your cells is a heavily guarded castle. For the SARS-CoV-2 virus, the notorious cause of COVID-19, breaking into this castle is the first step to launching an attack. We've long known that the virus picks the lock using its "key" (the spike protein) on a specific "door" (the ACE2 receptor). But what if the castle had a traitor inside, secretly greasing the hinges and making the door swing wide open?
Groundbreaking research suggests this is exactly what happens. Scientists have discovered that a molecule in our own cells, a long non-coding RNA named SNHG15, acts as this double agent, working with a cellular protein called RABL2A to dramatically boost the virus's ability to break in.
To understand this betrayal, we need to meet the key characters in this cellular drama.
Its goal is to enter our cells. Its tool is the spike protein, which latches onto the ACE2 receptor on the cell's surface.
Only about 1-2% of our DNA codes for proteins. The rest was once dismissed as "junk DNA," but we now know it's a vital control center, often called the "dark genome." A huge part of this is Long Non-Coding RNAs (lncRNAs). SNHG15 is one of these lncRNAs.
RABL2A is a protein that functions like a logistics manager for the ACE2 receptor. It helps transport the ACE2 receptor from inside the cell to the surface. The more ACE2 on the surface, the more doors the virus has to enter.
The discovery is that SNHG15 hijacks this system. It boosts the levels of the RABL2A protein, which in turn shuttles more ACE2 receptors to the cell surface, rolling out the red carpet for the virus.
How did scientists prove that SNHG15 was aiding the enemy? They conducted a series of elegant and decisive experiments.
The researchers used human lung cells (the primary target of the virus) and followed this process:
First, they infected lung cells with SARS-CoV-2 and used advanced genetic sequencing to see which lncRNAs became more active. SNHG15 was a top "suspect," as its levels shot up dramatically upon infection.
To confirm SNHG15's role, they used a technique called RNA interference (siRNA). Think of this as a precision-guided molecular scissor that can cut and destroy the SNHG15 RNA, effectively "knocking it down" without affecting other genes.
They kept a set of normal cells (the control group) and compared them to the cells where SNHG15 had been knocked down.
They exposed both sets of cells to a modified, safe-to-use version of the virus (a "pseudovirus") that still uses the ACE2 receptor to enter. This allowed them to measure viral entry accurately and safely.
The results were striking. In cells where SNHG15 was knocked down, viral entry plummeted. This was the first direct evidence that SNHG15 was essential for efficient infection.
But why? The team then looked at the ACE2 receptor. They found that in the SNHG15-deficient cells, there were far fewer ACE2 receptors on the cell surface. The "doors" were missing. This pointed to a problem with the "doorman," RABL2A.
Further experiments confirmed the entire pathway: SNHG15 stabilizes the instructions (mRNA) for making the RABL2A protein. More RABL2A protein means more ACE2 receptors are transported to the surface. More surface ACE2 means an easier entry for SARS-CoV-2.
This table shows the relative viral entry into lung cells under different conditions, measured by luminescence (a higher signal means more virus entered).
| Condition | Relative Viral Entry (%) |
|---|---|
| Control Cells (Normal SNHG15) | 100% |
| SNHG15 Knockdown Cells | 28% |
Silencing the SNHG15 gene led to a dramatic ~72% reduction in viral entry, proving its critical role in the infection process.
This data, measured by flow cytometry (a method to count protein levels on cells), shows how SNHG15 affects the number of viral "doors."
| Condition | Relative Surface ACE2 Level (%) |
|---|---|
| Control Cells (Normal SNHG15) | 100% |
| SNHG15 Knockdown Cells | 41% |
Knocking down SNHG15 caused a drastic decrease in the amount of ACE2 receptor present on the cell surface, explaining the reduced viral entry.
This table demonstrates the link between SNHG15 and the RABL2A protein.
| Condition | Relative RABL2A Protein Level (%) |
|---|---|
| Control Cells (Normal SNHG15) | 100% |
| SNHG15 Knockdown Cells | 45% |
The level of the RABL2A protein was cut by more than half when SNHG15 was removed, revealing that SNHG15's main job is to ensure high levels of RABL2A.
Comparison of key metrics between control cells and SNHG15 knockdown cells, showing the dramatic reduction in viral entry, surface ACE2, and RABL2A protein levels when SNHG15 is silenced.
This research relied on several key tools and reagents to uncover the truth.
| Research Tool | Function in the Experiment |
|---|---|
| siRNA (Small Interfering RNA) | A synthetic RNA molecule designed to bind to and trigger the degradation of a specific target RNA (like SNHG15), effectively "silencing" the gene. |
| SARS-CoV-2 Pseudovirus | A safe, engineered virus that carries the SARS-CoV-2 spike protein but cannot replicate. It is used to safely study the entry step of infection. |
| Antibodies (for ACE2 & RABL2A) | Specialized proteins that bind to a specific target protein (like a lock and key). Here, fluorescently tagged antibodies were used to detect and measure the levels of ACE2 and RABL2A. |
| qPCR (Quantitative Polymerase Chain Reaction) | A technique to measure the exact amount of a specific RNA molecule (like SNHG15 or RABL2A mRNA) in a cell sample. |
| Flow Cytometer | A sophisticated laser-based instrument that can count cells and measure the levels of specific proteins on their surface (like ACE2). |
The discovery of the SNHG15-RABL2A-ACE2 axis is more than just a fascinating molecular story. It opens up a completely new front in our understanding of and fight against COVID-19. By shifting the focus from the virus itself to the host cell's "dark genome," we uncover new vulnerabilities.
This pathway could explain why some people are more susceptible to severe infection and opens the door (pun intended) to entirely new therapeutic strategies. Instead of targeting the ever-mutating virus, what if we could develop a drug that temporarily disables the "double agent," SNHG15? By shutting down this cellular traitor, we could lock the doors to the castle, potentially protecting people from infection regardless of future viral variants. The battle against COVID-19 continues, but we now have a powerful new map of the battlefield—one that lies deep within our own cells.