Sequestosome-1 (P62/SQSTM1): A Multifunctional Protein in Cellular Homeostasis and Disease

Sequestosome-1 or SQSTM1 is a protein that’s essential, for maintaining balance in cells as well as being involved in autophage and signalling pathways. Originally identified as a protein that binds to proteins p62 has been found to be associated with different biological processes such as inflammation, oxidative stress and nerve degeneration.

Structure and Function

The P62 protein is a 62 kilodalton molecule coded by the SQSTM gene found on chromosome 5, in humans. Has functional regions that support its multiple functions.

The Ubiquitin associated (UBA) domain allows p62 to attach to polyubiquitinated proteins and serve as a platform, for protein accumulation and breakdown.

The Phox and Bem1 (PB1): PB ́Domain is responsible, for p62s ability to form dimers and interact with signalling proteins, in cell communication pathways.

The LC3 interacting region (LIR) enables p62 to connect with LC3 (microtubule associated protein 1 light chain 3) an autography protein that aids in shuttling materials to autography for breakdown purposes.

The structural characteristics of p62 allow it to serve as a connection, between proteins and autography mechanisms to help eliminate damaged or cellular elements.

Role in Autophagy

One of p62s roles is, in autophage activity – a process within cells that breaks down and reuses cell components when needed for maintaining balance, under stress or nutrient scarcity situations particularly crucial when a selective autophage receptor where it helps break down polyubiquitinated proteins and clumps of proteins.

• Autophage Formation: At the start of autophage activity p62 connects with LC3 to facilitate autophage formation. This procedure allows for capturing proteins and cell components to guide them for lysis breakdown, in lysosomes.
• Aggregation of Protein: Proteins clumping together, P62 plays a role gathering and clumping damaged or incorrectly folded proteins to help transport them to autophagosomes for disposal. This task is crucial, for overseeing protein quality control and stopping the buildup of clumps in cells.
• Regulation of Autophagic Flux: The level of p62 protein can impact how autophage works, higher p62 levels usually suggest that autophage is not working well as it should be It is common to see higher p62 levels, in diseases suggesting that it could be useful as a marker for problems, with autophage.

Involvement in Inflammatory Responses

In addition, to its function in processes p62 also plays a part, in controlling reactions. It has an ability to influence signalling routes linked to inflammation;

1. NF kappa B Signalling; P62 is known to engage with elements of NF kappa B signalling pathway by interacting with and hindering I kappa B kinase (IKK) complexes activity which can impact NF kappa B activation significantly. This connection highlights p62s involvement, in managing reactions in situations, like prolonged inflammation and cancer.
2. P62 is also involved in activating the NLRP3 inflammasome which’s crucial, for our body’s natural defence system against infections and illnesses by assisting in bringing signalling molecules to the inflammasome unit to boost the creation of inflammatory proteins, like IL-1beta and IL-18.
3. Oxidative stress is a process where P62 plays a role, in how cells respond to stress by regulating the production of antioxidant proteins and affecting signalling pathways to help protect cells from damage caused by oxidation.

Neurodegenerative Diseases

The protein P62 has attracted interest due to its role in conditions like Alzheimer’s disease and Parkinson’s disease well as amyotrophic lateral sclerosis (ALS). Researchers have noted an increase in P62 and protein clumps in patients’ brains affected by these diseases which implies a connection, between P62 malfunction and nerve cell degeneration.

In diseases, like Alzheimer’s or Parkinson’s disease; a key characteristic is when misfolded proteins such as tau and α-synuclein build up in an individual’s system leading to a cycle of aggregation due, to autophage pathways; P62 plays a role by sequestering these clumps but might end up accumulating itself if this process is disrupted.

Neuroinflammation is linked to increased p62 levels in conditions, where its involvement, in triggering inflammatory processes can lead to harm, to neurons and further advancement of neurodegeneration.

Targeting p62 and its interactions, with autolysis and inflammation could offer an approach, for treating illnesses by improving autolysis flow or adjusting p62 activity to lessen protein aggregate load and diminish neuroinflammation.

Cancer

Understanding how pivotal a player, like P62 is in cancer is no feat—it straddles a line between being a tumor suppressor and an oncogene depending on different scenarios such as autography and inflammation which makes it crucial, in unravelling cancers mysteries.

In some cases, p62 can help break down cancer causing proteins and stop cell growth hinting at its role, in fighting tumors.

On a note increased levels of p62 have been seen in types of cancer, where it might support tumor development and lifespan. P62 could boost NF kappa B signalling, resulting in cell division and resilience to cell death.

The potential of using p62 levels as a biomarker, for tumor progression and response to therapy is significant because of its dual roles in cancer treatment approaches may benefit from understanding how p62 functions in contexts, for tailoring treatments.

Suitable ELISA Kits

• Sequestosome-1 ELISA Kit
• P62/SQSTM1 ELISA Kit