Protein pivotal for B-cell cancers gets a closer look
Structural insights from cryo-electron microscopy could lead to drugs that target midnolin in leukemias, lymphomas, and multiple myelomas
DALLAS – June 09, 2025 – Using a cutting-edge imaging technology known as cryo-electron microscopy, researchers at UT Southwestern Medical Center have determined the structure of a protein called midnolin that’s crucial to the survival of malignant cells in some leukemias, lymphomas, and multiple myelomas. Their findings, published in PNAS, provide insight into how this protein functions in cells and could inform the design of new pharmaceuticals that avoid the serious side effects of current therapies.
“Seeing the structure of midnolin lends insight on how this protein helps cells dispose of other unneeded proteins in a way that’s different from the classical mechanism we’re used to seeing – a process that could have significant implications for cancer and immune-related diseases,” said Nagesh Peddada, Ph.D., Assistant Professor in the Center for the Genetics of Host Defense and of Immunology at UT Southwestern. He co-led the study with Bruce Beutler, M.D., Director of the Center for the Genetics of Host Defense and Professor of Immunology and Internal Medicine.
Dr. Beutler, who shared the 2011 Nobel Prize in Physiology or Medicine for his discovery of an important family of receptors found on immune cells, has long used mutagenesis – a method for introducing mutations into the genes of animal models – as a key approach for discovering the function of genes. Recently, the Beutler Lab pioneered a method known as automated meiotic mapping (AMM) that links abnormal traits in mutant mice to the mutations that cause them, thereby identifying genes needed to maintain a normal physiologic state.
Combining these tools, he and his colleagues reported last year that mutations in Midn, the gene that produces midnolin, protected mice genetically predisposed to developing B-cell leukemias and lymphomas. B cells, which are critical components of the adaptive immune system, divide out of control in these types of cancer. Using genetic tricks to eliminate or drastically reduce midnolin production significantly extended the affected animals’ lifespans by preventing them from developing these diseases at all.
Further experiments revealed that midnolin’s role in B cells is to ferry proteins to proteasomes, cellular organelles that degrade proteins that are damaged or no longer useful to the cell. Midnolin also stimulates proteasome activity, increasing the rate at which damaged proteins are removed from cells. Nearly all proteins routed to proteasomes are tagged for disposal by another protein called ubiquitin. However, proteins carried by midnolin aren’t tagged with ubiquitin, Dr. Peddada explained. How midnolin functions without ubiquitin’s help has been unclear.
Using UTSW’s Cryo-Electron Microscopy Facility, the researchers obtained three-dimensional images of midnolin bound to proteasomes at nearly atomic-level resolution. These images revealed key portions of midnolin that are critical for its partnership with proteasomes. One of these portions has a shape similar to ubiquitin that allows midnolin to open the same gateway in proteasomes that proteins must cross for their disposal.
Some therapies for B-cell leukemias and lymphomas work by inhibiting proteasome activity, Dr. Beutler explained. However, proteasome inhibitors come with a host of side effects, including gastrointestinal problems, decreased platelets that pose a bleeding risk, and nerve damage. Because midnolin is found primarily in B cells, developing drugs that block any of its actions could offer a safer alternative to proteasome inhibitors – a topic that the Beutler Lab plans to investigate in the future.
Other UTSW researchers who contributed to this study include Xiaochen Bai, Ph.D., Associate Professor of Biophysics and Cell Biology; Xue Zhong, Ph.D., Jin Huk Choi, Ph.D., and Eva Maria Y. Moresco, Ph.D., Assistant Professors in the Center for the Genetics of Host Defense and of Immunology; Yan Yin, Ph.D., Research Scientist; Danielle Renee Lazaro, B.S., Research Technician II; Jianhui Wang, M.S., Senior Research Scientist; and Stephen Lyon, M.A., Computational Research Scientist.
Dr. Beutler, a Regental Professor, holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr. He is also a member of the Cellular Networks in Cancer Research Program in the Harold C. Simmons Comprehensive Cancer Center at UTSW.
This research was funded by grants from the National Institutes of Health (R01AI125581) and The Welch Foundation (I-1944).
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.