New Cornell Study Reveals How SHKBP1 Fine-Tunes Cellular Stress Responses Through p62

On February 6, the Journal of Cell Biology published a Cornell study describing how cells keep one of their recycling systems from tipping out of balance. The work identifies an interaction between two proteins, SHKBP1 and p62, and shows that the first acts as a brake on the second.

The study was led by Lin Luan, a doctoral candidate in the Department of Biochemistry, Molecular and Cell Biology, and Jeremy Baskin, an associate professor of chemistry and chemical biology. Baskin holds the title of Nancy and Peter Meinig Family Investigator in the Life Sciences and is affiliated with both the College of Arts and Sciences and the Weill Institute for Cell and Molecular Biology. Two other doctoral students in his lab, Zijun Xia and Xiaofu Cao, contributed, as did collaborators at the Chan Zuckerberg Biohub. The Cornell Proteomics and Metabolomics Facility, part of the Cornell Biotechnology Resource Center, provided key support, and the National Institutes of Health funded the work.

Baskin describes p62 as a central player in cellular cleanup. Cells face constant stress, from ordinary metabolism and from insults in the environment, and p62 gathers damaged proteins into compartments called p62 bodies, where they can be dealt with. The difficulty, he said, is a Goldilocks problem. With too little p62 activity, toxic proteins can accumulate, as seen in Alzheimer's and Parkinson's disease. With too much, the system becomes overactive, which happens in many cancers, where tumor cells use the output of this recycling process to fuel their growth.

To see how the two proteins behave together, the team combined advanced biochemical and imaging techniques and watched them interact inside living cells. They found that SHKBP1 binds directly to the portion of p62 that normally lets it aggregate into large clusters. Because SHKBP1 occupies that region, p62 molecules are physically prevented from clumping into large bodies.

The experiments pointed in both directions. When SHKBP1 was removed, p62 bodies grew larger and less fluid. When extra SHKBP1 was added, the bodies became smaller and more dynamic.

The finding connects to the Keap1–Nrf2 pathway, a well-known antioxidant defense system that cells use against oxidative stress. Under normal conditions the system is balanced; under stress it switches on a protective response that limits cellular damage. p62 helps by removing a protein that suppresses that antioxidant response. According to the study, SHKBP1 influences the pathway indirectly, by controlling how p62 behaves and so helping set how strongly the protective response is activated.

The stakes show up in disease. Cancer cells often hijack this pathway to survive chemotherapy, while neurons in neurodegenerative disease may fail to activate it when they most need it.

Baskin stressed that the research was aimed at basic cellular mechanisms, but he sees connections to human disease that could eventually inform treatment. "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," he said. That is a hypothesis, not a result: no such drug has been tested, and the work so far describes how the proteins interact in cells. The next question is whether that interaction can be adjusted safely in disease.