SQSTM1 - Sequestosome-1 | Elisa - Clia - Antibody - Protein

Background

Sequestosome-1 (SQSTM1), also known as p62, is a multifunctional protein that plays a crucial role in various cellular processes, including autophagy, apoptosis, and inflammation. SQSTM1 is encoded by the SQSTM1 gene and is widely expressed in different tissues. It acts as a signaling hub, integrating signals from various pathways and mediating their effects on cellular functions. The protein is particularly known for its role in autophagy, a cellular degradation process that is vital for maintaining cellular homeostasis and responding to stress. Dysfunction in SQSTM1-related pathways has been implicated in numerous diseases, including neurodegenerative disorders, cancer, and Paget's disease of bone.

Protein Structure

SQSTM1 is characterized by several functional domains:

• Phox and Bem1p (PB1) Domain: Located at the N-terminus, this domain mediates self-oligomerization and interaction with other proteins containing PB1 domains.
• Zinc Finger (ZZ) Domain: Involved in binding to ubiquitinated proteins, crucial for its role in protein degradation.
• Tumor Necrosis Factor Receptor-Associated Factor 6 (TRAF6) Binding Domain: Facilitates interactions with TRAF6, playing a role in NF-κB signaling.
• Ubiquitin-Associated (UBA) Domain: Located at the C-terminus, this domain binds to polyubiquitin chains, targeting ubiquitinated proteins for autophagic degradation.

Classification and Subtypes

While SQSTM1 itself does not have subtypes, it is part of a larger family of ubiquitin-binding proteins that share similar roles in regulating protein degradation and signal transduction. These proteins often contain UBA domains and are involved in pathways related to protein homeostasis and stress responses.

Function and Biological Significance

SQSTM1 is involved in several key cellular processes:

• Autophagy: SQSTM1 acts as an autophagy receptor, recognizing and binding to ubiquitinated proteins and delivering them to autophagosomes for degradation. This process is essential for removing damaged proteins and organelles, thus maintaining cellular homeostasis.
• Signal Transduction: Through its interaction with TRAF6 and other signaling molecules, SQSTM1 participates in NF-κB signaling, which regulates immune responses, inflammation, and cell survival.
• Oxidative Stress Response: SQSTM1 is involved in the oxidative stress response by regulating the degradation of Keap1, a negative regulator of the transcription factor Nrf2, which is crucial for the antioxidant response.
• Apoptosis: SQSTM1 modulates apoptotic pathways by interacting with various signaling proteins and influencing their degradation.

Clinical Issues

Mutations and dysregulation of SQSTM1 are associated with several diseases:

• Paget's Disease of Bone: Mutations in the SQSTM1 gene are a major cause of this disorder, leading to abnormal bone remodeling and increased bone turnover.
• Neurodegenerative Diseases: SQSTM1 dysfunction is linked to diseases such as Alzheimer's, Huntington's, and amyotrophic lateral sclerosis (ALS), where impaired autophagy contributes to the accumulation of toxic protein aggregates.
• Cancer: Overexpression of SQSTM1 is observed in various cancers, where it may promote tumorigenesis by affecting autophagy and cell survival pathways.
• Inflammatory Diseases: SQSTM1 plays a role in chronic inflammatory conditions through its involvement in NF-κB signaling and regulation of cytokine production.

Summary

Sequestosome-1 (SQSTM1) is a multifunctional adaptor protein integral to autophagy, signal transduction, and apoptosis. Its structure includes key domains such as the PB1, ZZ, TRAF6 binding, and UBA domains, which facilitate interactions with various proteins and ubiquitin chains. SQSTM1's role in autophagy is critical for maintaining cellular homeostasis by degrading damaged proteins and organelles. Dysregulation or mutations in SQSTM1 are implicated in multiple diseases, including Paget's disease of bone, neurodegenerative disorders, cancer, and inflammatory conditions. Understanding SQSTM1's mechanisms offers potential therapeutic targets for these diseases.