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  3. Selective degradation of multimeric proteins by TRIM21-based molecular glue and PROTAC degraders

Selective degradation of multimeric proteins by TRIM21-based molecular glue and PROTAC degraders

  • Cell. 2024 Oct 30:S0092-8674(24)01197-8. doi: 10.1016/j.cell.2024.10.015.
Panrui Lu 1,  Yalong Cheng 2,  Lei Xue 1,  Xintong Ren 2,  Xilong Xu 3,  Chenglong Chen 2,  Longzhi Cao 3,  Jiaojiao Li 3,  Qingcui Wu 3,  Shan Sun 4,  Junjie Hou 5,  Wei Jia 5,  Wei Wang 3,  Yan Ma 1,  Zhaodi Jiang 1,  Chao Li 1,  Xiangbing Qi 1,  Niu Huang 6,  Ting Han 7
Affiliations

Affiliations

  • 1 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China; National Institute of Biological Sciences, Beijing 102206, China.
  • 2 National Institute of Biological Sciences, Beijing 102206, China; College of Life Sciences, Beijing Normal University, Beijing 100875, China.
  • 3 National Institute of Biological Sciences, Beijing 102206, China.
  • 4 State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structures, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 5 Deepkinase Co, Ltd, Beijing 102206, China.
  • 6 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China; National Institute of Biological Sciences, Beijing 102206, China. Electronic address: huangniu@nibs.ac.cn.
  • 7 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China; National Institute of Biological Sciences, Beijing 102206, China. Electronic address: hanting@nibs.ac.cn.
PMID: 39488207 DOI: 10.1016/j.cell.2024.10.015
Abstract

Targeted protein degradation (TPD) utilizes Molecular Glues or proteolysis-targeting chimeras (PROTACs) to eliminate disease-causing proteins by promoting their interaction with E3 ubiquitin ligases. Current TPD approaches are limited by reliance on a small number of constitutively active E3 ubiquitin ligases. Here, we report that (S)-ACE-OH, a metabolite of the antipsychotic drug acepromazine, acts as a molecular glue to induce an interaction between the E3 ubiquitin Ligase TRIM21 and the nucleoporin NUP98, leading to the degradation of nuclear pore proteins and disruption of nucleocytoplasmic trafficking. Functionalization of acepromazine into PROTACs enabled selective degradation of multimeric proteins, such as those within biomolecular condensates, while sparing monomeric proteins. This selectivity is consistent with the requirement of substrate-induced clustering for TRIM21 activation. As aberrant protein assemblies cause diseases such as autoimmunity, neurodegeneration, and Cancer, our findings highlight the potential of TRIM21-based multimer-selective degraders as a strategy to tackle the direct causes of these diseases.

Keywords

E3 ubiquitin ligase; PROTAC; TRIM21; biomolecular condensate; molecular glue; multimeric proteins; nuclear pore complex; targeted protein degradation.

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