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September 15, 2024

**P62: A Multifunctional Protein and Its Role in Cellular Processes**

P62, also known as Sequestosome 1 (SQSTM1), is a stress-inducible protein with multiple roles in cellular processes, particularly in autophagy, cell signaling, and protein degradation. This multifunctional protein acts as a vital regulator in cellular homeostasis, responding to various environmental stressors and playing a crucial part in maintaining cell function. Research from multiple scientific institutions, including *ScienceDirect*, *Nature*, and the *National Institutes of Health (NIH)*, has emphasized its importance in cellular pathways and disease mechanisms. In this article, we will explore the structure, function, and clinical relevance of p62, shedding light on its role in human health.

### Structure and Interaction of P62

At the molecular level, p62 is composed of several functional domains that allow it to interact with a wide range of signaling proteins. One key domain is the Phox and Bem1 (PB1) domain, which enables the formation of oligomers—both with itself and with other proteins. This oligomerization is essential for p62's role as a scaffolding protein, providing a platform for other signaling molecules to bind and interact. Additionally, the ubiquitin-associated (UBA) domain allows p62 to recognize and bind ubiquitinated proteins, marking them for degradation via autophagy or the proteasome system.

The structural studies published in *Nature* have revealed that p62 forms helical filaments, which are integral to its scaffolding functions. These helical filaments serve as the foundation for various cellular processes, particularly in protein degradation. The PB1 domain's ability to form these filaments is critical for autophagic cargo recognition and the formation of autophagosomes, specialized structures that degrade and recycle cellular components.

### P62's Role in Autophagy

One of the most well-known functions of p62 is its role in autophagy, a cellular process responsible for the degradation and recycling of damaged or unnecessary cellular components. Autophagy is essential for maintaining cellular homeostasis, especially under conditions of stress such as nutrient deprivation or the accumulation of misfolded proteins. P62 acts as an autophagy receptor, recognizing ubiquitinated proteins and directing them to autophagosomes for degradation.

A study by X. Huang, published on the *NIH* website, highlighted a key aspect of p62's role in autophagy: its ability to undergo S-acylation. This modification promotes the recruitment of p62 into liquid-like droplets, which are then selectively degraded by autophagy. These droplets, also known as p62 bodies, serve as platforms for the sequestration and degradation of ubiquitinated cargo. Without p62, these unwanted proteins can accumulate, leading to cellular dysfunction.

The research conducted by G. Bjørkøy et al., available on *ScienceDirect*, further elucidates the monitoring of p62 degradation through autophagy. It highlights techniques such as Western blotting and pulse-chase analysis, which help track the half-life and degradation rate of p62. When autophagy is inhibited, p62 accumulates, serving as a marker for autophagic dysfunction. This makes p62 a valuable tool for researchers studying autophagy-related diseases.

### P62 in Cell Signaling Pathways

Beyond its role in autophagy, p62 is heavily involved in multiple cell signaling pathways. It acts as a key mediator in the nuclear factor kappa B (NF-κB) signaling pathway, which regulates inflammation, immune response, and cell survival. P62 interacts with tumor necrosis factor receptor-associated factors (TRAFs) and other signaling molecules to modulate the activity of NF-κB. By regulating this pathway, p62 can influence a range of cellular processes, from inflammation to cell death.

Another signaling pathway where p62 plays a crucial role is the mechanistic target of rapamycin complex 1 (mTORC1) pathway. This pathway regulates cell growth, metabolism, and protein synthesis in response to nutrient availability. P62 interacts with the mTORC1 complex, helping cells adapt to changing metabolic conditions. This interaction is particularly important in the context of aging and age-related diseases, where nutrient sensing and cellular metabolism become dysregulated.

A study published in *Frontiers in Aging Neuroscience* emphasized the importance of p62 in aging and neurodegenerative diseases. P62's role in regulating cellular stress responses and protein aggregation makes it a pivotal player in diseases such as Alzheimer's and Parkinson's. The accumulation of misfolded proteins and the failure of autophagic processes are hallmarks of these diseases, and p62 is often found in the protein aggregates associated with neurodegeneration.

### P62 and Human Disease

P62 has been implicated in a variety of human diseases, ranging from cancer to neurodegenerative disorders. Its role in autophagy and protein degradation is particularly relevant in the context of these diseases, where the accumulation of damaged proteins or dysfunctional cellular components can lead to cellular stress and death.

In cancer, p62 is often upregulated in tumor cells, where it promotes cell survival and proliferation. By activating the NF-κB and mTORC1 pathways, p62 helps cancer cells adapt to the stressful conditions of the tumor microenvironment. This makes p62 a potential therapeutic target in cancer treatment, as inhibiting its activity could reduce tumor growth and enhance the effectiveness of chemotherapy.

In contrast, in neurodegenerative diseases such as Alzheimer's and Huntington's disease, p62's role is often protective. By facilitating the degradation of toxic protein aggregates, p62 helps prevent the accumulation of misfolded proteins that can damage neurons. However, in some cases, p62 itself becomes sequestered in these aggregates, preventing it from performing its normal functions. This dual role of p62—as both a protector and a participant in disease—highlights the complexity of its involvement in human health.

Mutations in the *SQSTM1* gene, which encodes p62, have been linked to several hereditary diseases, including Paget's disease of bone and amyotrophic lateral sclerosis (ALS). These mutations can disrupt p62's normal functions, leading to impaired autophagy and protein degradation. Understanding the molecular mechanisms underlying these mutations is an active area of research, with the goal of developing targeted therapies for these conditions.

### Conclusion

P62 is a multifunctional protein with a wide range of roles in cellular processes, particularly in autophagy and cell signaling. Its ability to act as a scaffolding protein and recognize ubiquitinated proteins makes it a key player in maintaining cellular homeostasis. The research conducted by leading scientific institutions, including *ScienceDirect*, *Nature*, and the *NIH*, has provided valuable insights into the structure, function, and clinical relevance of p62.

As a central regulator of autophagy and cell signaling, p62 has been implicated in a variety of human diseases, from cancer to neurodegeneration. Its dual role in promoting cell survival in some contexts and facilitating the degradation of toxic proteins in others makes it a promising target for therapeutic intervention. Understanding the complex biology of p62 will continue to be an important focus of research, with the potential to yield new treatments for a range of diseases.