Unlocking the Secrets of PELI2: A New Player in Autoimmunity

The innate immune system serves as our body's first line of defense against pathogens and cellular stress. One of the key players in this system is the cGAS-STING pathway - an early sentinel that sounds the alarm to activate the immune system when danger is detected. While crucial for antiviral and antitumor responses, dysregulation of this pathway can lead to severe autoimmune diseases.

So how does the STING pathway know when to fight and when to stand down?

The latest research from Dr. Lingyin Li’s lab, published in Molecular Cell, reveals a previously unknown mechanism that keeps our immune system in check. At the heart of this discovery is PELI2, a protein that prevents the STING pathway from overreacting to small amounts of cellular stress.

"Our immune system faces a constant challenge," explained Li, an Arc Core Investigator and Stanford University Associate Professor of Biochemistry. "It needs to respond robustly to real threats while avoiding overreaction to minor cellular disturbances. We've found that PELI2 plays a crucial role in maintaining this delicate balance."

The STING pathway functions as a cellular alarm system, detecting danger signals such as double-stranded DNA (dsDNA) in the cytoplasm—the part of the cell outside the nucleus where DNA doesn't normally reside. This misplaced DNA can occur due to viral infections or cancer, but low levels can also appear in benign conditions such as a sun tan or the normal aging process. The team's research focused on understanding what prevents the STING pathway from being triggered by small fluctuations of misplaced dsDNA, and what causes it to sound the alarm.

"Our findings showed that PELI2 filters out cellular 'white noise' that could chronically trigger STING, potentially leading to inflammatory conditions like lupus and neurodegeneration,” explained the study’s lead author, postdoctoral researcher Chris Ritchie. "Conversely, when the body encounters a real threat such as a viral infection, PELI2 levels decrease, effectively amplifying the real signal and allowing the STING pathway to react effectively."

Unraveling PELI2's Function

Interested in identifying potential STING regulators, Ritchie and Li employed a diverse array of experimental techniques, starting with a series of genetic screens. The screens consistently highlighted PELI2, opening a new avenue for exploration.

"This initial finding was a signpost that PELI2 was worth a deeper look, but to understand its actual impact on STING, we needed to understand the molecular mechanisms at play," Ritchie noted. "To do that, we used a combination of experimental approaches that wove together biochemistry with structural and cellular biology.”

Through protein interaction studies, the researchers discovered that PELI2 binds to specific sites on the STING protein. This binding allows PELI2 to inhibit a key step in the STING signaling cascade by disabling another protein called TBK1, a critical enzyme that cooperates with STING to activate the immune response. This effectively puts the brakes on the STING pathway without permanently destroying it, allowing it to still be activated whenever there are real threats.

After validating these findings in a physiological context, they found that cells with reduced PELI2 were more likely to trigger a strong immune response even with basal levels of DNA damage, while cells with higher levels of PELI2 showed a reduced immune reaction.

Complementing these findings, the researchers observed that PELI2 levels decrease precipitously during viral infections, allowing for a more robust immune response when needed—and that individuals with certain autoimmune conditions, like lupus, had lower levels of PELI2 at baseline, priming them for overactive STING signaling.

"Our findings suggest that without sufficient PELI2 to filter out cellular noise, certain autoimmune patients may experience chronic, unnecessary activation of the STING pathway,” Li explained. “This discovery opens up new avenues for understanding and potentially treating autoimmune conditions and preventing aging related inflammation.”

Looking Ahead

The Li Lab now looks to expand their investigation of PELI2's role in autoimmunity and aging. They plan to explore how PELI2 levels are regulated in different cell types and disease states, and whether manipulating PELI2 activity could have therapeutic potential.

Additionally, the team is curious about how this mechanism might play a role in other STING-related conditions, such as certain cancers where STING activation is beneficial. This line of inquiry could lead to new strategies for enhancing anti-tumor immunity.

"While there's still much to learn,” shared Li. “We're excited about the potential implications of our findings and by how this curiosity-driven research has led to unexpected insights that could unlock new therapies for patients suffering from autoimmune conditions.”