Institute of Science Tokyo elucidates new substrate recognition mechanism in degradation of unnecessary intracellular proteins

A research team led by Project Professor Shigeomi Shimizu and Project Assistant Professor Yoichi Nibe-Shirakihara from the Department of Pathological Cell Biology, Advanced Research Initiative, Institute of Integrated Research at the Institute of Science Tokyo, in collaboration with the Department of Gastroenterology and Hepatology at the Institute of Science Tokyo, Hiroshima University, and Monash University in Australia, announced on October 16 that they have clarified how a new Golgi membrane-associated degradation mechanism (GOMED) selects and degrades substrates. GOMED is known to be involved in various diseases, and this discovery is expected to lead to the development of new therapeutic approaches for these conditions. The results were published in Nature Communications on October 20.

Within cells, mechanisms such as autophagy exist to maintain homeostasis by degrading unnecessary proteins and organelles. GOMED is one such mechanism, utilizing Golgi membranes to degrade unnecessary components. Since it functions in all cells that constitute the human body, dysfunction in GOMED has been reported as a potential cause of neurodegenerative diseases and other conditions. However, how GOMED recognizes and degrades substrates remained unclear.

For this study, the research group conducted analysis assuming that at least one of the five molecules known to perform substrate recognition during protein degradation might be involved. They found that optineurin (OPTN) was crucial.

Next, when they investigated what markers OPTN uses to recognize substrates, they discovered that it functions by targeting K33 chains formed by ubiquitin molecules (Ub). Furthermore, they revealed that OPTN and K33 ubiquitin also function in mitochondrial removal during the final differentiation process of red blood cells.

It is known that K48Ub is important for protein degradation by the proteasome, while K63Ub and linear Ub are crucial for degradation through autophagy. In contrast, degradation through GOMED can be positioned as a new "third protein degradation system."

Nibe and Shimizu commented, "Our laboratory discovered 'GOMED,' a new mechanism by which cells process their own proteins, and has been clarifying its functions and relationship to disease. GOMED functions in all cells and plays a fundamental role in maintaining life. This achievement represents an important step toward deepening our understanding. Going forward, we will work to elucidate the various diseases caused by GOMED dysfunction and connect this to the creation of unprecedented therapeutic and diagnostic approaches."

Journal Information
Publication: Nature Communications
Title: Optineurin is an adaptor protein for ubiquitinated substrates in Golgi membrane-associated degradation
DOI: 10.1038/s41467-025-64400-3