p62 is a protein found in cells. It plays a fundamental role in maintaining cellular health and balance, influencing various biological processes. Understanding p62 offers insights into cellular mechanisms.
What is p62?
p62, also known as sequestosome 1 (SQSTM1), is a protein found in virtually all human cells. Its name comes from its approximate molecular weight of 62 kilodaltons.
This protein is described as an “adaptor” or “scaffolding” protein, meaning it acts as a linker, bringing different cellular components together. p62 achieves this through distinct domains that allow it to bind to various molecules.
p62’s Core Functions
One of p62’s primary roles involves its participation in selective autophagy, the cell’s recycling or waste disposal system. In this process, p62 acts as a linker. It recognizes and binds to unwanted cellular components, such as damaged proteins or organelles, that have been tagged with ubiquitin.
Once bound to these ubiquitinated cargoes, p62 delivers them to specialized cellular structures called autophagosomes for degradation. This function is facilitated by p62’s ubiquitin-associated domain (UBA) that binds ubiquitin, and its LC3-interacting region (LIR) that binds to proteins on the autophagosome membrane. This system ensures efficient removal of cellular debris. For instance, p62 clears protein aggregates (aggrephagy) and aids in removing damaged mitochondria (mitophagy).
Beyond waste disposal, p62 also functions as a signaling hub, integrating cellular signals. It contains domains that interact with signaling activators, modulating diverse pathways. For example, p62 can activate the NF-κB pathway, involved in inflammatory responses, by interacting with atypical protein kinase C (aPKC).
It also participates in the Keap1-Nrf2 pathway, central to the cell’s antioxidant response. p62 interacts with Keap1, leading to the activation of Nrf2 and the expression of genes that protect cells from oxidative stress. Through these interactions, p62 helps cells respond to stresses and maintain cellular balance.
p62 in Health and Disease
The proper functioning of p62 contributes to maintaining cellular health, while its dysregulation can have implications in various diseases. When p62’s ability to clear cellular waste or regulate signaling pathways is impaired, it can contribute to disease development. This makes p62 a subject of research in understanding disease mechanisms.
In neurodegenerative diseases, p62’s role in clearing protein aggregates is relevant. Conditions like Alzheimer’s, Parkinson’s, and Huntington’s disease are characterized by the accumulation of misfolded proteins in brain cells. p62 helps clear these harmful aggregates, and its dysfunction can exacerbate their buildup, contributing to neuronal damage and disease progression. For instance, p62 has been observed in neuronal and glial inclusions in human tauopathies and synucleinopathies.
p62 also has a complex and context-dependent role in cancer. In some instances, it can act as a tumor suppressor by promoting the clearance of damaged proteins and organelles that might otherwise contribute to uncontrolled cell growth. However, in other contexts, p62 can act as a tumor promoter by activating pro-survival signaling pathways, such as NF-κB, which can support cancer cell proliferation and survival. Abnormal fusion proteins involving the SQSTM1 gene have also been linked to cancer.
Furthermore, p62 is implicated in chronic inflammation and metabolic disorders like obesity and type 2 diabetes. Its involvement in these conditions is often linked to its signaling functions, particularly its ability to modulate inflammatory pathways like NF-κB. Understanding p62’s balance in these processes is important, as its proper regulation is intertwined with the body’s metabolic and inflammatory responses.
Research and Future Directions
Ongoing research continues to uncover the intricate roles of p62 in cellular biology and disease. Scientists are actively investigating p62’s potential as a biomarker, which could indicate disease progression or cellular stress levels. Changes in p62 levels often reflect the activity of cellular degradation pathways, making it a useful indicator for researchers.
Researchers are also exploring ways to modulate p62 activity, for example, through pharmacological interventions, as a potential therapeutic strategy for various conditions. This involves investigating compounds that might enhance p62’s beneficial functions or inhibit its detrimental activities, depending on the specific disease context. This area of research holds significant promise for developing new approaches to understand and treat a range of human diseases.