SQSTM1, or sequestosome 1, is a protein found throughout the body that plays a significant role in maintaining the normal operations of cells. It contributes to the body’s ability to recycle worn-out cell parts and unneeded proteins, a process known as autophagy. This protein helps ensure cells properly manage their internal environment.
Understanding SQSTM1
SQSTM1 is also recognized by its alternative name, p62. The SQSTM1 gene provides instructions for its creation. It is a multi-domain protein, with regions capable of interacting with different cellular components. These domains include:
- An N-terminal Phox and Bem1p (PB1) domain
- A ZZ-type zinc finger domain
- A TRAF6-binding (TB) domain
- A Keap1-interaction region (KIR)
- A C-terminal ubiquitin-associated (UBA) domain
The PB1 domain allows p62 to self-associate and form long, flexible filaments.
This protein is found in the cytoplasm and can also be present in the nucleus. Its diverse domains allow p62 to function as an “adaptor” or “scaffold” protein, connecting various molecules and pathways within the cell. It acts as a central hub for signal integration and diversification.
The Many Roles of SQSTM1 in Cells
SQSTM1, or p62, functions prominently as a selective autophagy receptor, a process where cells break down and recycle damaged components. It identifies specific cellular “cargo,” such as proteins tagged with ubiquitin chains, and delivers them to autophagosomes for degradation. The protein’s UBA domain specifically binds to these polyubiquitinated proteins, while its LC3-interacting region (LIR) connects to LC3, a protein on the autophagosomal membrane, effectively bridging the cargo to the degradation machinery. This mechanism ensures the removal of harmful protein aggregates and old organelles, maintaining cellular quality control.
Beyond its role in autophagy, p62 also participates in other important cellular signaling pathways. It is involved in the NF-κB pathway, which regulates inflammation and immune responses. In this context, p62 acts as an adaptor by interacting with various proteins like atypical protein kinase C (PKC), receptor-interacting protein 1 (RIP1), and tumor necrosis factor receptor-associated factor 6 (TRAF6), influencing the activation of this pathway.
P62 also plays a part in the Keap1-Nrf2 pathway, a system for responding to oxidative stress. SQSTM1 interacts with Keap1, a protein that promotes Nrf2 degradation. By binding to Keap1, p62 inhibits its ability to degrade Nrf2, leading to Nrf2 stabilization and activation. This activation then promotes the expression of genes that protect cells from oxidative damage.
SQSTM1 is also involved in the formation and clearance of protein aggregates. It can form structures called p62 bodies, found as cytoplasmic inclusions containing ubiquitinated proteins. These bodies can be either free in the cytosol or contained within autophagosomes and lysosomes, indicating their role in sequestering and facilitating the degradation of misfolded or aggregated proteins. This function is important for cellular health, preventing the accumulation of toxic protein clumps.
SQSTM1’s Link to Disease
Dysregulation or mutations in SQSTM1 are linked to several human diseases, reflecting its broad cellular functions. A primary association is with Paget’s disease of bone (PDB), a disorder characterized by abnormal bone remodeling. Mutations in the SQSTM1 gene are a common genetic cause of PDB, with the most frequent mutation being a change from proline to leucine at position 392 (P392L). These mutations appear to overactivate a signaling pathway that promotes the formation of osteoclasts, the cells responsible for breaking down bone tissue. This leads to an accelerated breakdown and replacement of bone, resulting in new bone tissue that is weaker and more disorganized than normal bone.
SQSTM1 dysfunction also contributes to neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS), Parkinson’s disease, and Alzheimer’s disease. In these conditions, impaired p62 function can lead to the accumulation of toxic protein aggregates within neurons. The protein’s role in selective autophagy means that its malfunction can hinder the clearance of misfolded or damaged proteins, which then aggregate and contribute to neuronal damage and disease progression.
The involvement of SQSTM1 in cancer is complex and multifaceted. Depending on the cellular context, it can act as both a tumor suppressor and an oncogene. For instance, the SQSTM1 gene can be found in fusion proteins, where it abnormally combines with genes like tyrosine kinases, leading to uncontrolled cell proliferation and cancer. Conversely, p62’s role in the Keap1-Nrf2 pathway and in clearing protein aggregates can also contribute to tumor suppression, highlighting its dual nature in disease.