Article Impact Level: HIGH Data Quality: STRONG Summary of Proceedings of the National Academy of Sciences, 122(19), e2505345122. https://doi.org/10.1073/pnas.2505345122 Dr. Nagesh Peddada et al.
Points
- Researchers at UT Southwestern used cryo-electron microscopy to reveal how midnolin enhances proteasome activity by binding to RPN11 and RPN1, promoting protein degradation without relying on ubiquitin tagging.
- The study demonstrated that midnolin is essential for the survival of malignant B cells, with Midn-mutant mice showing protection from leukemia and lymphoma along with significantly extended lifespans.
- Unlike traditional pathways, midnolin directly delivers substrates to the proteasome, bypassing ubiquitin tagging and offering a new mechanism for protein degradation in B-cell malignancies.
- Targeting midnolin-proteasome interactions could provide a safer alternative to conventional proteasome inhibitors, which often cause severe side effects like neuropathy and gastrointestinal distress.
- These findings open promising avenues for developing more selective and tolerable therapies against B-cell cancers by inhibiting midnolin rather than blocking the entire proteasome system.
Summary
A study conducted by researchers at UT Southwestern Medical Center aimed to investigate the role of midnolin (MIDN) in facilitating proteasome activity, which is critical for the survival of B-lymphoid malignancies, including certain leukemias and lymphomas. Using cryo-electron microscopy (cryo-EM), the team elucidated the atomic structure of the MIDN-proteasome complex, revealing the mechanism by which MIDN enhances proteasomal degradation of unneeded proteins in a ubiquitin-independent manner. The research showed that MIDN binds to two distinct regions of the proteasome, employing a ubiquitin-like domain to interact with the deubiquitinase RPN11 and a C-terminal α-helix to engage with RPN1, positioning its substrate-carrying domain above the proteasome’s ATPase channel.
In the study, MIDN’s ability to support proteasomal function was critical for the survival of malignant B cells in mice predisposed to B-cell leukemias and lymphomas. Mice with mutations in the Midn gene were protected from these diseases, demonstrating a significant lifespan extension. The cryo-EM images provided a high-resolution view of the key protein-protein interactions, highlighting how MIDN, unlike the classical ubiquitin-dependent pathway, can deliver substrates to the proteasome for degradation without tagging them with ubiquitin. This breakthrough opens new avenues for therapeutic targeting of MIDN in treating B-cell malignancies, which could avoid the severe side effects of conventional proteasome inhibitors.
The findings suggest that inhibiting MIDN’s interaction with the proteasome could offer a targeted and safer alternative to proteasome inhibition therapies, which are currently associated with adverse effects like gastrointestinal issues, thrombocytopenia, and neuropathy. The research lays the groundwork for future investigations into MIDN’s role in cancer therapy and its potential to offer more selective treatment options for patients with B-cell cancers without the side effects typical of proteasome inhibition.
Link to the article: https://www.pnas.org/doi/10.1073/pnas.2505345122
References Peddada, N., Zhong, X., Yin, Y., Lazaro, D. R., Wang, J., Lyon, S., Choi, J. H., Bai, X., Moresco, E. M. Y., & Beutler, B. (2025). Structural insights into the ubiquitin-independent midnolin-proteasome pathway. Proceedings of the National Academy of Sciences, 122(19), e2505345122. https://doi.org/10.1073/pnas.2505345122
