Cells are constantly navigating a complex landscape of stressors, from the byproducts of normal metabolism to external environmental challenges. A newly published study from Cornell University sheds light on a crucial mechanism cells use to manage this stress, revealing a previously unknown interaction between two proteins – SHKBP1 and p62 – that helps maintain a vital cellular recycling system. The findings, published on , in the Journal of Cell Biology, could have implications for understanding and potentially treating diseases like cancer and neurodegenerative disorders.
The research centers on p62, a protein essential for clearing damaged cellular components and activating the body’s antioxidant defenses. This process is akin to a cellular recycling operation, gathering damaged proteins into structures called “p62 bodies” where they can be safely broken down. However, maintaining the right level of p62 activity is critical. Too little activity leads to the accumulation of toxic proteins, a hallmark of diseases like Alzheimer’s and Parkinson’s. Conversely, excessive p62 activity can be exploited by cancer cells to fuel tumor growth.
“The key challenge for p62 is a Goldilocks problem,” explains Jeremy Baskin, associate professor in the Department of Chemistry and Chemical Biology at Cornell University. “With too little activity, toxic proteins can accumulate, which is seen in Alzheimer’s and Parkinson’s disease. With too much p62 activity, the system becomes overactive, which happens in many cancers, as cancer cells use the output of this recycling process to fuel tumor growth.”
The Cornell team, led by doctoral candidate Lin Luan, used advanced biochemical and imaging techniques to observe how SHKBP1 and p62 interact within living cells. Their investigation revealed that SHKBP1 directly binds to a region of p62 responsible for its aggregation into larger clusters. This binding action physically prevents p62 molecules from clumping together to form p62 bodies.
“What we found was that SHKBP1 binds directly to a portion of p62 that normally allows it to aggregate into large clusters, so SHKBP1 binding physically prevented p62 molecules from clustering together into large bodies,” Baskin said. “Removing SHKBP1 caused p62 bodies to grow larger and less fluid, while adding extra SHKBP1 made them smaller and more dynamic.”
The study also illuminates how this interaction influences the Keap1–Nrf2 pathway, a well-established antioxidant defense system. This pathway is normally balanced, but activates a protective response when cells encounter stress, limiting cellular damage. P62 plays a role in this process by removing a protein that suppresses the antioxidant response. The research demonstrates that SHKBP1 indirectly regulates this system by controlling p62’s behavior, thereby influencing the strength of the protective response.
The implications of these findings extend to several disease areas. Cancer cells frequently hijack the Keap1–Nrf2 pathway to survive chemotherapy, while in neurodegenerative diseases, neurons may fail to activate this pathway when it’s most needed. Understanding how SHKBP1 modulates this balance could therefore open new avenues for therapeutic intervention.
Researchers identified SHKBP1 as a critical regulator of p62 activity, demonstrating the importance of maintaining balance between the two proteins for effective stress management. The study also provides insight into the role of these proteins in clearing damaged cell components and activating antioxidant defenses.
“Understanding how SHKBP1 influences this balance could open new therapeutic avenues,” Baskin said. “If loss of SHKBP1 function naturally boosts the Nrf2 response, perhaps we could develop drugs that safely inhibit SHKBP1 in the brain to provide neuroprotection.”
The research team included Zijun Xia and Xiaofu Cao, doctoral students in Baskin’s lab and collaborators at the Chan Zuckerberg Biohub. The study benefited from key support from the Cornell Proteomics and Metabolomics Facility within the Cornell Biotechnology Resource Center and was funded by the National Institutes of Health. Further research will be needed to fully elucidate the therapeutic potential of targeting the SHKBP1-p62 interaction, but this discovery represents a significant step forward in understanding the intricate mechanisms cells use to cope with stress and maintain cellular health.
The study also identified a specific protein-protein interaction outside of p62 bodies, which limits p62 assembly and affects the antioxidant response involving sequestration of Keap1 and nuclear translocation of Nrf2, according to research published in PubMed.
