The p62 protein (Sequestosome 1 or SQSTM1) acts as a multi-functional cellular adaptor. This protein is a central hub, containing several distinct domains that allow it to interact with a wide array of binding partners. Functionally, p62 links cellular cleanup processes and signaling pathways that govern cell survival and stress response. Its dual nature allows it to regulate the degradation of cellular waste while simultaneously modulating key transcriptional programs. Because of this central role, p62 dysregulation is implicated in the development and progression of numerous human diseases.
p62 as an Autophagy Receptor
The foundational role of p62 is functioning as a selective autophagy receptor, ensuring the targeted removal of specific cellular components. Selective autophagy is the cellular housekeeping process responsible for clearing damaged organelles, misfolded proteins, and toxic aggregates. p62 acts as the molecular bridge connecting the waste material to the degradation machinery.
p62 first recognizes the cargo destined for destruction using its C-terminal Ubiquitin-Associated (UBA) domain, which binds specifically to polyubiquitin chains tagging the damaged material. p62 then utilizes its Phox and Bem1p (PB1) domain to self-associate and form large clusters. This oligomerization concentrates the tagged waste, increasing the efficiency of the subsequent engulfment process.
The aggregated p62-cargo complex is delivered to the nascent autophagosome, a double-membraned vesicle. This delivery is mediated by the LC3-Interacting Region (LIR) domain of p62, which binds directly to LC3 anchored to the autophagosome membrane.
This LIR-LC3 interaction physically tethers the ubiquitinated cargo. Once the autophagosome fuses with a lysosome, the entire complex is degraded by lysosomal enzymes. Because p62 is degraded along with its cargo, its cellular level serves as a biochemical marker inversely proportional to the activity of the autophagic pathway.
p62 and Cellular Signaling Pathways
Beyond degradation, p62 serves as a scaffold to coordinate cell signaling, a role independent of its receptor activity. The multi-domain structure allows p62 to aggregate signaling molecules, activating pathways that influence cell survival and stress tolerance. This scaffolding function positions p62 as a direct regulator of gene expression.
p62 regulates the Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, which manages the cellular response to oxidative stress. Normally, Keap1 binds to Nrf2 and targets it for degradation. However, p62 contains a Keap1-Interacting Region (KIR) domain that allows it to bind competitively to Keap1.
When p62 levels rise, the protein sequesters Keap1, preventing Nrf2 degradation. This stabilization allows Nrf2 to translocate to the nucleus, where it activates the transcription of protective genes responsible for detoxification and antioxidant production. This p62-Keap1-Nrf2 axis enhances the cell’s capacity to cope with environmental stressors.
p62 also acts as a positive regulator of the Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway, a master regulator of inflammation and immune responses. The p62 scaffold facilitates the assembly of a signaling complex that includes the TRAF6-binding (TB) domain. This complex leads to the activation of the NF-kB transcription factor, promoting persistent inflammatory signaling.
Connecting p62 Dysfunction to Pathology
The balance between p62’s role in degradation and signaling means its dysregulation is a significant factor in numerous disease states. When autophagic machinery fails, p62 levels increase, leading to detrimental accumulation. This accumulation drives both the failure to clear toxic aggregates and the chronic activation of pro-survival pathways.
In neurodegenerative conditions, such as Alzheimer’s and Parkinson’s disease, p62 accumulates within characteristic protein inclusion bodies. The failure to efficiently clear these toxic aggregates, often due to impaired LIR or UBA domain function, contributes directly to synaptic dysfunction and progressive neuronal death.
In many types of cancer, high levels of p62 actively promote tumor survival and proliferation. The accumulation suppresses the degradation of damaged proteins while activating NF-kB and Nrf2 signaling. NF-kB activation fuels chronic tumor-associated inflammation, and Nrf2 activation provides cancer cells with a robust antioxidant defense, allowing them to withstand oxidative stress.
This mechanism is evident in liver diseases, where p62 is a component of Mallory-Denk bodies (MDBs) found in patients with alcoholic and non-alcoholic steatohepatitis (ASH/NASH). The sustained accumulation of p62 is linked to chronic liver inflammation and progression toward hepatocellular carcinoma (HCC). The presence of these inclusion bodies is often used as a prognostic biomarker.
Modulating p62 for Therapeutic Benefit
Given its central role linking degradation and signaling, p62 is an attractive target for novel therapeutic strategies. The goal is to modulate p62 activity to restore cellular balance in diseased tissues. One strategy involves developing small molecules designed to enhance p62’s function as an autophagy receptor.
Researchers are exploring compounds that potentiate the binding efficiency of the LIR domain to LC3, accelerating the autophagic clearance of toxic aggregates in neurodegenerative disorders. Conversely, in cancer, therapies are being developed to disrupt the pro-survival signaling complexes formed by p62. This includes designing inhibitors that block the interaction between p62 and TRAF6, suppressing the pro-inflammatory NF-kB pathway.
Another emerging approach focuses on inhibiting the p62-Keap1 interaction to modulate the Nrf2 pathway. Blocking p62-mediated Nrf2 activation in cancer cells could strip them of their antioxidant defense, making them more vulnerable to chemotherapy. The specificity of the various p62 domains—UBA, LIR, KIR, and TB—offers multiple distinct points of intervention for precise tuning of degradation and signaling pathways.