Within our cells operates a quality control and recycling system known as autophagy. This process is responsible for cellular housekeeping, breaking down and reusing old or damaged components to maintain health. Central to this system is a protein officially named Sequestosome-1 (SQSTM1), but more commonly known as p62. This protein functions as a shuttle, identifying and transporting cellular waste to the recycling machinery. The function of p62 is connected to human health, and disruptions in its activity are implicated in a range of diseases, including neurodegeneration and cancer.
The Function of p62 in Selective Autophagy
Autophagy often operates with high specificity in a process termed selective autophagy. This precision is necessary for targeting particular items for disposal, such as misfolded proteins or damaged organelles. The protein p62 drives this selectivity, acting as a cargo receptor that connects unwanted material to the cell’s disposal machinery. It functions like a bridge with two distinct binding capabilities, similar to having two hands for different jobs.
One part of the p62 protein is designed to grab onto cellular waste. This waste is first marked for destruction with a protein tag called ubiquitin. The C-terminal ubiquitin-associated (UBA) domain of p62 recognizes and binds to these polyubiquitinated targets. This ensures that only materials the cell has designated as waste are collected, protecting healthy components from accidental degradation.
The other part of p62 interacts with the recycling machinery itself—a vesicle called the autophagosome. It does this by binding to the protein LC3, which is embedded in the autophagosome’s membrane. This interaction is mediated by a region on p62 known as the LC3-interacting region (LIR). By simultaneously holding onto the ubiquitinated cargo and the LC3-decorated autophagosome, p62 tethers the waste to the disposal unit, ensuring it is engulfed by the forming vesicle.
Once the cargo is inside the autophagosome, the vesicle fuses with an organelle called the lysosome. The lysosome contains enzymes that break down the contents, including the cargo and p62 itself, into reusable components. Without p62 acting as this essential connector, tagged cellular waste is not efficiently delivered to the autophagosome. This leads to its accumulation and potential toxicity within the cell.
p62 as a Marker for Autophagic Activity
Because p62 is consumed with the cargo it transports, its abundance provides a snapshot of autophagic efficiency. Scientists measure p62 levels to assess autophagic flux, which is the overall rate of degradation. The relationship is inverse: when autophagy runs efficiently, p62 is continuously broken down, resulting in low cellular levels of the protein.
An accumulation of p62 indicates a problem. High p62 levels suggest the autophagic pathway is blocked after p62 has bound to its cargo. This blockage could be due to a failure in autophagosome formation, its fusion with the lysosome, or reduced lysosomal enzyme activity. In these scenarios, p62 and its cargo are not degraded and build up inside the cell.
To draw an analogy, if autophagy is a city’s trash collection service, p62 represents the full trash cans left for pickup. A street with very few full cans indicates the collection service is working effectively. However, a street lined with overflowing trash cans signals a breakdown in the system, indicating a problem in waste removal.
By monitoring p62 levels, often with the autophagosome protein LC3, researchers gain a more complete picture of autophagic activity. An increase in both LC3 and p62 suggests a blockage in the final degradation steps. This method allows for a functional assessment of the entire pathway, providing insights into how cellular stress or disease might impact this housekeeping process.
The Link Between p62 and Neurodegeneration
The consequences of faulty p62-mediated autophagy are severe in long-lived, non-dividing cells like neurons. These cells are vulnerable to the buildup of misfolded proteins, which can become toxic. When selective autophagy fails, these proteins are not cleared and form insoluble protein aggregates, a hallmark of many neurodegenerative diseases.
These protein clumps, which contain p62, contribute to the pathology of neurological disorders. In Alzheimer’s disease, a failure to clear the protein tau leads to neurofibrillary tangles inside neurons. In Parkinson’s disease, the accumulation of alpha-synuclein protein results in Lewy bodies. In both cases, p62 is a prominent component of these toxic aggregates, showing it was the receptor that attempted but failed to clear them.
The presence of p62 within these aggregates indicates a stalled cleaning process. The cell correctly identifies and tags the toxic proteins, and p62 binds to them. However, a downstream failure in the autophagic machinery prevents their disposal. This implicates a breakdown in autophagy in the progression of the disease.
This accumulation of toxic proteins damages and kills neurons, leading to the progressive loss of brain function. Studies have shown that a p62 deficiency can accelerate neurodegeneration, confirming its protective role in maintaining neuron health. The failure of this cleaning service is a direct contributor to the pathology of neurodegeneration, not just a symptom.
The Dual Role of p62 in Cancer
The role of p62 and autophagy in cancer is complex and context-dependent. The pathway can both suppress and promote tumor development, depending on the disease stage and cellular environment. This duality makes targeting p62 or autophagy in cancer treatment a challenge.
In healthy cells or during the early stages of cancer, p62-mediated autophagy acts as a tumor suppressor. By clearing damaged organelles and other sources of cellular stress, autophagy helps prevent DNA mutations that can lead to cancer. In this context, p62 is part of a quality control system that maintains genomic stability.
Once a tumor is established, cancer cells can hijack the autophagic pathway for survival. Tumors often face harsh conditions like nutrient deprivation and low oxygen. Cancer cells upregulate p62-mediated autophagy to adapt, recycling their own components to generate nutrients and energy to sustain proliferation and resist treatments.
This functional switch means p62 can act as a tumor promoter in advanced cancers. High levels of p62 are observed in various tumors and are often associated with poor patient prognosis. This complex, stage-dependent function complicates therapeutic strategies aimed at this pathway.