Ubiquitin receptor-mediated, ubiquitin-independent targeted protein degradation via 26S proteasomes.

Authors

Seh Hoon Park, Yejin Jang, Soo-Yeon Lee, Eunseo Kim, Dawon Jeong, Insuk Byun, Jiseong Kim, Jisoo Yang, Chang-Han Lee, Dohyun Han, Jae-Hwan Nam, Min Jae Lee

Published in

Science advances. Volume 12. Issue 38. Pages eaeh0227. Sep 18, 2026. Epub Sep 18, 2026.

Abstract

The 26S proteasome engages with ubiquitinated substrates primarily through its constituent ubiquitin (Ub) receptors, which initiates a cascade of proteolytic processes. Leveraging this recognition mechanism, we developed a targeted protein degradation (TPD) strategy that recruits substrates directly to the proteasome, thereby bypassing the ubiquitination step. Our proteasome-targeting chimera, Protea-Tac, is a heterobifunctional protein degrader composed of a Ub receptor and an intracellular antibody. This chimera integrates into 26S proteasomes without altering their structural or functional integrity. Protea-Tac with cognate antibodies degraded various target proteins, including c-Fos, BRD4, ^FlagTDP43, ^HAtau, and ^GFPODC. We mechanistically demonstrated that this platform is (i) modular, allowing facile target switching, (ii) Ub independent, and (iii) highly target specific. Furthermore, Protea-Tac exhibited potent in vivo antitumor efficacy, posttranslationally inducing c-Fos degradation and substantially delaying tumor progression through both viral and nonviral delivery systems. These findings identify Protea-Tac as a distinct TPD platform capable of directly degrading intracellular proteins via engineered 26S proteasomes.

PMID:
42758827
Bibliographic data and abstract were imported from PubMed on 19 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.