SQSTM1

Overview

SQSTM1 (Sequestosome 1) is a multifunctional protein encoded by the SQSTM1 gene in humans. It is also known as p62, and it plays a crucial role in various cellular processes, including autophagy, cell signaling, and the regulation of oxidative stress. SQSTM1 is involved in the degradation of ubiquitinated proteins and is a key player in the selective autophagy pathway.

Structure

SQSTM1 is a 440 amino acid protein with several functional domains:

• PB1 domain: Involved in protein-protein interactions, particularly in oligomerization and interaction with other PB1 domain-containing proteins.
• ZZ-type zinc finger domain: Facilitates binding to ubiquitin.
• TB (TRAF6-binding) domain: Interacts with TRAF6, a key adaptor protein in the NF-κB signaling pathway.
• LIR (LC3-interacting region) motif: Essential for binding to LC3, a protein involved in autophagosome formation.
• UBA (ubiquitin-associated) domain: Binds to polyubiquitin chains, targeting proteins for degradation.

Function

SQSTM1 serves as a scaffold protein that links ubiquitinated proteins to the autophagic machinery. It is involved in:

• Autophagy: SQSTM1 acts as a cargo receptor, recognizing ubiquitinated proteins and facilitating their degradation via autophagy. It binds to LC3 on the autophagosome membrane, promoting the engulfment of cargo.
• Cell signaling: It participates in various signaling pathways, including the NF-κB pathway, by interacting with TRAF6 and other signaling molecules.
• Oxidative stress response: SQSTM1 is involved in the regulation of oxidative stress by modulating the activity of the antioxidant response element (ARE) and interacting with Keap1, a regulator of the Nrf2 pathway.

Clinical Significance

Mutations in the SQSTM1 gene have been associated with several diseases, including:

• Paget's disease of bone: A disorder characterized by abnormal bone remodeling, where mutations in SQSTM1 lead to increased osteoclast activity.
• Amyotrophic lateral sclerosis (ALS): Some mutations in SQSTM1 have been linked to familial forms of ALS, a neurodegenerative disease affecting motor neurons.
• Frontotemporal dementia (FTD): Mutations in SQSTM1 are also associated with FTD, a form of dementia affecting the frontal and temporal lobes of the brain.

Research and Therapeutic Potential

SQSTM1 is a target of interest in research due to its role in autophagy and cell signaling. Modulating SQSTM1 activity could have therapeutic potential in diseases characterized by protein aggregation, such as neurodegenerative disorders.

Also see

• Autophagy
• Ubiquitin-proteasome system
• NF-κB signaling pathway
• Paget's disease of bone
• Amyotrophic lateral sclerosis
• Frontotemporal dementia