Kaye Awarded NIH Grant to Study Immune Protein

Jonathan Kaye, PhD

A Cedars-Sinai immunologist has been awarded a two-year, $413,325 grant by the National Institutes of Health to analyze how a protein, known as TOX, helps create and maintain a healthy immune system. One of the study's goals is to yield insights that potentially could lead to new cancer therapies.

The immunologist, Jonathan Kaye, PhD, vice chair of the Department of Biomedical Sciences and director of its Research Division of Immunology, is working with colleagues to understand the structure and function of TOX, short for "thymocyte selection-associated high mobility group box protein." This protein is found in the nucleus of immune cells, including natural killer (NK) cells, which help identify and destroy other cells that are malignant or infected with viruses.

In previous research using animal models, Kaye's laboratory has demonstrated that NK and many other types of immune cells fail to develop in TOX-deficient mice, indicating that this nuclear protein is a critical building block of the immune system. TOX appears to help regulate gene expression during development of NK cells.

However, it is not entirely clear, at the molecular level, how TOX works its magic. That is what the NIH-funded study seeks to discover.

Kaye and his colleagues plan to test a hypothesis that the TOX molecule changes its interior spatial arrangement, or conformation, when it binds to the DNA in the nucleus of an NK cell. They then plan to determine how certain genetic mutations influence this DNA binding and how these mutations may alter the function of the protein as it regulates gene expression.

These experiments, which will include protein structure determination, biophysical measurements and cellular assays for protein function, will be performed in vitro.

The research relies on pioneering work by Kaye's laboratory in collaboration with Ramachandran Murali, PhD, an associate professor of biomedical sciences who directs Cedars-Sinai's Molecular Therapeutics Core. Together, the two labs recently determined the crystal structure of the DNA-binding domain of TOX. Murali also is collaborating on the new study, for which Kaye is the principal investigator.

While specific in nature, the NIH-funded project has broad potential for future therapeutic application, said Kaye, the study's principal investigator, who also is a professor of biomedical sciences and medicine and a member of the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute. "Natural killer cells play important roles in tumor surveillance and can be harnessed for cancer immunotherapies," he explained.

By shedding light on the molecular mechanism of the TOX nuclear protein, Kaye's research may one day help clinical scientists identify ways to enhance NK cell development and make the cells more effective in battling malignancies.