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Assaying Proteasomal Degradation in a Cell-free System in Plants

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Proteasome Cap Targeting Chimeras for Ubiquitination-Independent Targeted Protein Degradation.

Chen Song^1,2, Qi Liu^1,2, Tingjian Wang^1,2

¹Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.

Angewandte Chemie (International Ed. in English)

|January 20, 2026

Summary

Researchers developed Proteasome Cap Targeting Chimeras (CAP-TACs) to directly recruit disease proteins to the proteasome. This novel strategy achieves targeted protein degradation without ubiquitination, offering a simpler therapeutic approach.

Keywords:

CAP‐TAC Proteasome cap region protein induced degradation RPN13 induced degradation Small molecule recruiter to proteosome Ubiquitination independent degradation

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Last Updated: Jan 22, 2026

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Detection of Protein Ubiquitination

Detection of Protein Ubiquitination

Published on: August 19, 2009

Area of Science:

Molecular Biology
Drug Discovery
Proteasome Biology

Background:

Targeted protein degradation is a key therapeutic strategy.
Current methods use E3 ligases and ubiquitination, which are complex.
Direct proteasome recruitment offers a simpler alternative.

Purpose of the Study:

To evaluate direct recruitment of non-ubiquitinated proteins to the proteasome.
To develop small molecules for this purpose.
To demonstrate ubiquitination-independent degradation of disease proteins.

Main Methods:

Utilized a tag strategy to identify proteasome binding sites.
Developed Proteasome Cap Targeting Chimeras (CAP-TACs).
Tested CAP-TACs on various disease-associated proteins (BRD4, PRMT5, FKBP12).

Main Results:

RPN13 and RPN1 proteins can recruit non-ubiquitinated proteins to the proteasome.
CAP-TACs successfully recruited distinct proteins to the 19S proteasome cap.
Induced ubiquitination-independent, proteasome-dependent degradation of target proteins.

Conclusions:

Direct proteasome recruitment is feasible for targeted protein degradation.
CAP-TACs offer a novel, simplified approach to protein degradation therapy.
This broadens the scope of targeted protein degradation strategies.