Secretion is a second fate for p62 and is coupled to KEAP1/NRF2 signaling
This study reveals that p62 undergoes continuous secretion via PB1-mediated oligomerization as a second fate alongside lysosomal degradation, a process that co-regulates KEAP1 release and modulates the NRF2-mediated oxidative stress response.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer
Inside every living cell, a constant cleanup crew works to maintain order. This system, known as autophagy, acts like a recycling plant, identifying worn-out proteins and damaged parts, wrapping them up, and sending them to a specialized compartment called the lysosome to be broken down and discarded. This process is vital for health; without it, toxic waste accumulates, leading to cellular dysfunction and disease. For decades, scientists believed this was the only fate for the proteins involved in this cleanup: they were either recycled or destroyed. However, a growing body of evidence suggests that cells have a second way of dealing with their internal cargo, one that involves sending materials out into the surrounding environment rather than breaking them down. This alternative path, often called secretory autophagy, is poorly understood, and researchers have struggled to track exactly which proteins take this route, how much of them leave the cell, and what happens when they do.
A team of researchers at Hirosaki University in Japan has now shed light on this hidden exit route, focusing on a key protein called p62. This protein acts as a manager in the cell's cleanup system, gathering other proteins that need to be disposed of and tagging them for the recycling plant. The scientists wanted to know if p62 itself ever escapes the cell. The challenge was that p62 is present in very small amounts outside the cell, making it nearly impossible to detect with standard tools, and trying to force the cell to produce more of it often creates artificial clumps that distort the results. To solve this, the team developed a clever method to tag the cell's natural p62 with a tiny, invisible marker that glows when it meets a specific partner. This allowed them to track the protein with extreme sensitivity without altering its natural behavior or overwhelming the cell.
Using this precise tracking system, the researchers discovered that p62 is constantly leaving the cell, packaged inside tiny, sealed bubbles that float out into the surrounding fluid. This happens at a steady rate, comparable to the rate at which another well-known marker of the cleanup system, called LC3B, is released. The study showed that this release is not a one-time event but a continuous process. When the researchers blocked the cell's internal recycling plant, preventing the usual breakdown of waste, the amount of p62 being sent outside the cell increased significantly. This suggests that when the internal trash can is full or broken, the cell opens a back door to expel the excess.
The team also investigated how this exit happens. They found that for p62 to leave the cell, it must first stick to itself, forming larger clumps or chains. This self-assembly is essential; if the protein cannot stick to itself, it stays trapped inside. Surprisingly, the protein does not need to bind directly to the recycling machinery to be exported, nor does it need to bind to a specific partner protein called KEAP1, which is involved in protecting the cell from stress. Instead, the act of p62 clumping together seems to be the main signal that sorts it for export. This finding challenges the idea that p62 is only a passenger on a specific recycling vehicle; instead, its own structure determines its fate.
Furthermore, the researchers discovered that KEAP1, the protein that partners with p62 to manage the cell's response to oxidative stress, is also exported in these same bubbles. When the researchers blocked the exit route for these bubbles, KEAP1 remained stuck inside the cell, and the cell's ability to respond to stress signals was dampened. This implies that the continuous export of these proteins is not just a way to get rid of waste, but a functional part of how the cell communicates its internal state and manages stress. By removing KEAP1 and p62 from the cytoplasm, the cell may be fine-tuning its sensitivity to damage.
The study confirms that p62 leaves the cell through at least two parallel paths: one that relies on the core machinery of the recycling system and another that operates independently. While the exact molecular machinery that fuses these bubbles with the cell's outer wall remains to be fully mapped, the work establishes that the export of p62 and its partners is a real, measurable, and biologically significant process. This discovery adds a new layer to our understanding of cellular health, showing that cells do not just destroy their internal components but also actively release them, potentially influencing the environment around them and the behavior of neighboring cells. The ability to track these low-abundance proteins with such precision opens the door to studying other mysterious secretory pathways, offering a clearer view of how cells manage their internal economy and interact with the world outside.
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