The p62 protein is a versatile cellular component that helps maintain overall cellular balance. It interacts with diverse molecules, participating in numerous cellular processes essential for proper cell function.
What is p62 Protein?
The p62 protein, also known as sequestosome 1 (SQSTM1), is a multi-domain protein found mainly in the cytoplasm and also in the nucleus. Its structure includes an N-terminal PB1 domain, a ZZ-type zinc finger domain, a nuclear localization signal (NLS), an export motif (NES), an LC3-interacting region (LIR), a KEAP1-interacting region (KIR), and a C-terminal ubiquitin-associated (UBA) domain. These domains allow p62 to interact with many other proteins and cellular components.
The PB1 domain enables p62 to self-assemble into flexible filaments and oligomers. The UBA domain specifically binds to polyubiquitinated proteins, which are marked for degradation. The LIR motif connects p62 with LC3 proteins, components of the autophagosome membrane, linking cargo to the degradation machinery.
Primary Roles in Cellular Housekeeping
p62 serves as a selective autophagy receptor. Autophagy is a process where cells engulf and break down damaged proteins, organelles, and invading pathogens within double-membraned vesicles called autophagosomes. p62 recognizes ubiquitinated cargo, which are cellular components tagged with ubiquitin chains, through its UBA domain.
Once bound to ubiquitinated cargo, p62 interacts with the autophagosome membrane via its LC3-interacting region (LIR). This interaction recruits the targeted waste into the forming autophagosome. The autophagosome then fuses with a lysosome, forming an autolysosome, where the cargo is broken down and recycled. This selective autophagy process maintains cellular health by removing harmful or unnecessary components. p62’s levels inversely correlate with autophagic degradation; when autophagy is impaired, p62 can accumulate, forming aggregates with ubiquitinated proteins.
p62’s Role in Cellular Communication
Beyond waste removal, p62 acts as a signaling hub, influencing various cellular responses. It interacts with several signaling molecules and pathways through its different domains. For example, p62 can activate the NF-κB pathway, involved in inflammation, immunity, and cell survival. It does this by interacting with TRAF6, a protein involved in NF-κB activation, and promoting its ubiquitination.
p62 also activates the Nrf2 pathway, a defense mechanism against oxidative stress. p62 binds to Keap1, an inhibitor of Nrf2, leading to Nrf2 stabilization and nuclear translocation. This activates genes that protect cells from oxidative damage. p62 can also influence the mTORC1 pathway, which regulates cell proliferation and differentiation.
p62 and Disease
Dysregulation of p62’s functions in autophagy and signaling has implications in various human diseases. In cancer, p62 is often overexpressed in many tumor types, including breast, prostate, and hepatocellular carcinoma. While autophagy can suppress tumors by eliminating damaged components, p62’s accumulation due to defective autophagy can promote tumorigenesis by altering NF-κB regulation and gene expression. In this context, p62 can support cancer cell survival and contribute to tumor progression.
In neurodegenerative disorders, misfolded and aggregated proteins commonly accumulate. p62 is frequently found in these protein aggregates, such as those seen in Alzheimer’s, Parkinson’s, Huntington’s diseases, and amyotrophic lateral sclerosis (ALS). In these conditions, p62’s role as an autophagy receptor is important because it helps anchor ubiquitinated proteins to the autophagosome for degradation. For instance, in models of dementia, p62 has been shown to play a neuroprotective role by eliminating neurotoxic tau protein aggregates, which, if left unchecked, can lead to neuronal degeneration and inflammation.