Chemically induced USP21-KLHL12 association recruits USP21 to COPII assembly

Abstract

Ubiquitin-specific protease 21 (USP21) is a deubiquitinase implicated in various biological processes and disease states, including cancer. To better understand USP21 protein interaction networks, we used biotin identification proximity labeling, and uncovered USP21 interactions with the cytoskeleton, endosomal, and transcriptional regulators. Notably, a subset of these interactions was modulated by the USP21 selective inhibitor BAY-805. In cells, BAY-805 promoted proximity between USP21 and Kelch like protein KLHL12, a component of the Cullin3 ligase complex. Structural modeling using AlphaFold3, together with hydrogen deuterium exchange mass spectrometry, identified an orthosteric BAY-805 binding site within USP21. Binding of BAY-805 functionally competes with ubiquitin at USP21, thereby enabling USP21 interaction with KLHL12. This BAY-805 induced proximity elicited relocalization of USP21 to KLHL12 containing coat protein complex II (COPII) vesicles. Induced USP21-KLHL12 association led to enlargement of COPII vesicles and impaired transport of large cargoes such as collagen. Overall, our findings reveal a novel chemically induced proximity mechanism in which the monovalent ligand BAY-805 outcompetes ubiquitin from USP21, thereby recruiting USP21 to KLHL12 associated protein complexes.

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BibTeX

@misc{vu2026chemically,
  title = {{Chemically induced USP21-KLHL12 association recruits USP21 to COPII assembly}},
  author = {V. Vu and M. Kanaris and E. Wolf and S. Keller and Q. Liu and C. V. Simoben and S. Ahmad and V. Rebber and M. M. Szewczyk and P. Loppnau and M. E. Maitland and E. C. Adamson and P. Picotti and D. Wilson and C. H. Arrowsmith and L. Halabelian and M. Schapira and M. Gstaiger and R. J. Harding and D. Barsyte-Lovejoy},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.13.750941},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.13.750941v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Chemically induced USP21-KLHL12 association recruits USP21 to COPII assembly
AU  - V. Vu
AU  - M. Kanaris
AU  - E. Wolf
AU  - S. Keller
AU  - Q. Liu
AU  - C. V. Simoben
AU  - S. Ahmad
AU  - V. Rebber
AU  - M. M. Szewczyk
AU  - P. Loppnau
AU  - M. E. Maitland
AU  - E. C. Adamson
AU  - P. Picotti
AU  - D. Wilson
AU  - C. H. Arrowsmith
AU  - L. Halabelian
AU  - M. Schapira
AU  - M. Gstaiger
AU  - R. J. Harding
AU  - D. Barsyte-Lovejoy
PY  - 2026
DA  - 2026/09/13
PB  - bioRxiv
DO  - 10.64898/2026.09.13.750941
UR  - https://www.biorxiv.org/content/10.64898/2026.09.13.750941v1
AB  - Ubiquitin-specific protease 21 (USP21) is a deubiquitinase implicated in various biological processes and disease states, including cancer. To better understand USP21 protein interaction networks, we used biotin identification proximity labeling, and uncovered USP21 interactions with the cytoskeleton, endosomal, and transcriptional regulators. Notably, a subset of these interactions was modulated by the USP21 selective inhibitor BAY-805. In cells, BAY-805 promoted proximity between USP21 and Kelch like protein KLHL12, a component of the Cullin3 ligase complex. Structural modeling using AlphaFold3, together with hydrogen deuterium exchange mass spectrometry, identified an orthosteric BAY-805 binding site within USP21. Binding of BAY-805 functionally competes with ubiquitin at USP21, thereby enabling USP21 interaction with KLHL12. This BAY-805 induced proximity elicited relocalization of USP21 to KLHL12 containing coat protein complex II (COPII) vesicles. Induced USP21-KLHL12 association led to enlargement of COPII vesicles and impaired transport of large cargoes such as collagen. Overall, our findings reveal a novel chemically induced proximity mechanism in which the monovalent ligand BAY-805 outcompetes ubiquitin from USP21, thereby recruiting USP21 to KLHL12 associated protein complexes.
ER  -

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