Cellular Stress Regulation Discovery: A New Mechanism Identified

Cornell University researchers have identified a new mechanism by which cells regulate their response to stress. This discovery involves an interaction between two proteins, SHKBP1 and p62, which helps maintain balance within a critical cellular recycling system.

The Central Role of p62 Protein

The protein p62 is central to cellular recycling, responsible for clearing damaged cell components and activating antioxidant defenses. This process requires a precise balance:

Insufficient p62 activity can lead to the accumulation of toxic proteins, observed in diseases such as Alzheimer's and Parkinson's. Conversely, excessive p62 activity can overactivate the system, contributing to tumor growth in various cancers.

SHKBP1's Regulatory Function Unveiled

The study found that SHKBP1 directly binds to a part of p62 that typically allows it to form large clusters, known as 'p62 bodies.' This binding prevents p62 molecules from clustering excessively. When SHKBP1 was removed, p62 bodies became larger and less fluid. When extra SHKBP1 was added, they became smaller and more dynamic, highlighting SHKBP1's role in controlling p62 body dynamics.

Impact on Antioxidant Defense Pathway

Cells utilize the Keap1–Nrf2 pathway as an antioxidant defense system. p62 plays a role in this pathway by aiding the removal of a protein that suppresses the antioxidant response. The research indicates that SHKBP1 indirectly influences this system by controlling p62's behavior, thereby affecting the strength of the protective response activation. Disruptions in this pathway are noted in cancer, where cells exploit it for survival, and in neurodegenerative diseases, where activation may be insufficient.

Potential Therapeutic Implications

Though focused on fundamental cellular mechanisms, these findings have connections to human diseases.

Understanding how SHKBP1 affects this cellular balance could lead to new therapeutic approaches.

For instance, inhibiting SHKBP1 in the brain might offer neuroprotection by boosting the Nrf2 response, suggesting a potential target for treating certain neurological conditions.