Mapping the IMiD-dependent cereblon interactome using BioID-proximity labelling.

Costacurta, M; Sandow, JJ; Maher, B; Susanto, O; Vervoort, SJ; Devlin, JR; Garama, D; Condina, MR; Steele, JR; Kahrood, HV; Gough, D; Johnstone, RW; Shortt, J

Mapping the IMiD-dependent cereblon interactome using BioID-proximity labelling.

Costacurta, M Sandow, JJ Maher, B Susanto, O Vervoort, SJ Devlin, JR Garama, D Condina, MR Steele, JR Kahrood, HV Gough, D Johnstone, RW Shortt, J

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Publisher:: Wiley
Publication Type:: Journal Article
Citation:: FEBS J, 2024, 291, (22), pp. 4892-4912
Issue Date:: 2024-11

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Field	Value	Language
dc.contributor.author	Costacurta, M
dc.contributor.author	Sandow, JJ
dc.contributor.author	Maher, B
dc.contributor.author	Susanto, O
dc.contributor.author	Vervoort, SJ
dc.contributor.author	Devlin, JR
dc.contributor.author	Garama, D
dc.contributor.author	Condina, MR
dc.contributor.author	Steele, JR
dc.contributor.author	Kahrood, HV
dc.contributor.author	Gough, D
dc.contributor.author	Johnstone, RW
dc.contributor.author	Shortt, J
dc.date.accessioned	2025-06-10T09:14:34Z
dc.date.available	2024-05-24
dc.date.available	2025-06-10T09:14:34Z
dc.date.issued	2024-11
dc.identifier.citation	FEBS J, 2024, 291, (22), pp. 4892-4912
dc.identifier.issn	1742-464X
dc.identifier.issn	1742-4658
dc.identifier.uri	http://hdl.handle.net/10453/187679
dc.description.abstract	Immunomodulatory imide drugs (IMiDs) are central components of therapy for multiple myeloma (MM). IMiDs bind cereblon (CRBN), an adaptor for the CUL4-DDB1-RBX1 E3 ligase to change its substrate specificity and induce degradation of 'neosubstrate' transcription factors that are essential to MM cells. Mechanistic studies to date have largely focussed on mediators of therapeutic activity and insight into clinical IMiD toxicities is less developed. We adopted BioID2-dependent proximity labelling (BioID2-CRBN) to characterise the CRBN interactome in the presence and absence of various IMiDs and the proteasome inhibitor, bortezomib. We aimed to leverage this technology to further map CRBN interactions beyond what has been achieved by conventional proteomic techniques. In support of this approach, analysis of cells expressing BioID2-CRBN following IMiD treatment displayed biotinylation of known CRBN interactors and neosubstrates. We observed that bortezomib alone significantly modifies the CRBN interactome. Proximity labelling also suggested that IMiDs augment the interaction between CRBN and proteins that are not degraded, thus designating 'neointeractors' distinct from previously disclosed 'neosubstrates'. Here we identify Non-Muscle Myosin Heavy Chain IIA (MYH9) as a putative CRBN neointeractor that may contribute to the haematological toxicity of IMiDs. These studies provide proof of concept for proximity labelling technologies in the mechanistic profiling of IMiDs and related E3-ligase-modulating drugs.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Wiley
dc.relation.ispartof	FEBS J
dc.relation.isbasedon	10.1111/febs.17196
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0304 Medicinal and Biomolecular Chemistry, 0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics
dc.subject.classification	Biochemistry & Molecular Biology
dc.subject.classification	3101 Biochemistry and cell biology
dc.subject.classification	3205 Medical biochemistry and metabolomics
dc.subject.classification	3404 Medicinal and biomolecular chemistry
dc.subject.mesh	Humans
dc.subject.mesh	Adaptor Proteins, Signal Transducing
dc.subject.mesh	Ubiquitin-Protein Ligases
dc.subject.mesh	Bortezomib
dc.subject.mesh	Multiple Myeloma
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Thalidomide
dc.subject.mesh	Protein Interaction Maps
dc.subject.mesh	Proteomics
dc.subject.mesh	Immunologic Factors
dc.subject.mesh	Lenalidomide
dc.subject.mesh	Protein Interaction Mapping
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Humans
dc.subject.mesh	Multiple Myeloma
dc.subject.mesh	Thalidomide
dc.subject.mesh	Ubiquitin-Protein Ligases
dc.subject.mesh	Adaptor Proteins, Signal Transducing
dc.subject.mesh	Immunologic Factors
dc.subject.mesh	Protein Interaction Mapping
dc.subject.mesh	Proteomics
dc.subject.mesh	Protein Interaction Maps
dc.subject.mesh	Bortezomib
dc.subject.mesh	Lenalidomide
dc.subject.mesh	Humans
dc.subject.mesh	Adaptor Proteins, Signal Transducing
dc.subject.mesh	Ubiquitin-Protein Ligases
dc.subject.mesh	Bortezomib
dc.subject.mesh	Multiple Myeloma
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Thalidomide
dc.subject.mesh	Protein Interaction Maps
dc.subject.mesh	Proteomics
dc.subject.mesh	Immunologic Factors
dc.subject.mesh	Lenalidomide
dc.subject.mesh	Protein Interaction Mapping
dc.title	Mapping the IMiD-dependent cereblon interactome using BioID-proximity labelling.
dc.type	Journal Article
utslib.citation.volume	291
utslib.location.activity	England
utslib.for	0304 Medicinal and Biomolecular Chemistry
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1101 Medical Biochemistry and Metabolomics
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Provost
pubs.organisational-group	University of Technology Sydney/Provost/Jumbunna
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2025-06-10T09:14:32Z
pubs.issue	22
pubs.publication-status	Published
pubs.volume	291
utslib.citation.issue	22

Abstract:

Immunomodulatory imide drugs (IMiDs) are central components of therapy for multiple myeloma (MM). IMiDs bind cereblon (CRBN), an adaptor for the CUL4-DDB1-RBX1 E3 ligase to change its substrate specificity and induce degradation of 'neosubstrate' transcription factors that are essential to MM cells. Mechanistic studies to date have largely focussed on mediators of therapeutic activity and insight into clinical IMiD toxicities is less developed. We adopted BioID2-dependent proximity labelling (BioID2-CRBN) to characterise the CRBN interactome in the presence and absence of various IMiDs and the proteasome inhibitor, bortezomib. We aimed to leverage this technology to further map CRBN interactions beyond what has been achieved by conventional proteomic techniques. In support of this approach, analysis of cells expressing BioID2-CRBN following IMiD treatment displayed biotinylation of known CRBN interactors and neosubstrates. We observed that bortezomib alone significantly modifies the CRBN interactome. Proximity labelling also suggested that IMiDs augment the interaction between CRBN and proteins that are not degraded, thus designating 'neointeractors' distinct from previously disclosed 'neosubstrates'. Here we identify Non-Muscle Myosin Heavy Chain IIA (MYH9) as a putative CRBN neointeractor that may contribute to the haematological toxicity of IMiDs. These studies provide proof of concept for proximity labelling technologies in the mechanistic profiling of IMiDs and related E3-ligase-modulating drugs.

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http://hdl.handle.net/10453/187679