Research Highlights
A new mechanism of protein degradation: revealing how the proteasome recognizes branched ubiquitin chains

An international research team led by Dr. Shang-Te Danny Hsu at the Institute of Biological Chemistry, Academia Sinica, has for the first time resolved the high-resolution cryo-electron microscopy (cryo-EM) structure of the human 26S proteasome bound to a branched K11/K48-linked ubiquitin chain, uncovering how the proteasome precisely identifies proteins destined for rapid degradation.

The study reveals that the RPN2 subunit of the proteasome contains a previously unrecognized K11-specific ubiquitin-binding site, which works together with RPN8, RPN10, and the known K48-binding region on RPT4/5 to form a multi-site recognition interface. This architecture allows the proteasome to effectively capture branched ubiquitin chains and initiate targeted protein degradation. These findings shed light on how cells maintain protein homeostasis through complex ubiquitin signaling and provide crucial molecular insight into cellular quality control mechanisms.

This research was supported by Academia Sinica and the National Science and Technology Council (NSTC), Taiwan. Key technical assistance was provided by the Academia Sincia Cryo-EM Center and the Proteomics Mass Spectrometry Common Facility (PMSCF) at Academia Sinica.

The first author, Piotr Draczkowski, was supported by the Academia Sinica Postdoctoral Fellowship (2017–2020) and a follow-up NSTC grant (2021–2022). The paper was published on October 15, 2025, in Nature Communications and was selected by the editors as an Editor’s Highlight.

Article title: title: Structural basis of K11/K48-branched ubiquitin chain recognition by the human 26S proteasome

Link to the publication: https://doi.org/10.1038/s41467-025-64719-x

Authors: Draczkowski P, Chen SN, Chen T, Wang YS, Shih HA, Huang JYC, Tsai MC, Lin SY, Lin S, Viner R, Chang YC, Wu KP, Hsu STD*