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  The IMiD target CRBN determines HSP90 activity toward transmembrane proteins essential in multiple myeloma

Heider, L., Eichner, R., Stroh, J., Morath, V., Kuisl, A., Zecha, J., et al. (2021). The IMiD target CRBN determines HSP90 activity toward transmembrane proteins essential in multiple myeloma. Molecular Cell, 81(6), 1170-1186.e10. doi:10.1016/j.molcel.2020.12.046.

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 Creators:
Heider, L.1, Author
Eichner, Ruth1, Author
Stroh, Jacob1, Author
Morath, Volker1, Author
Kuisl, Anna1, Author
Zecha, Jana1, Author
Lawatscheck, Jannis1, Author
Baek, Kheewong2, Author              
Garz, Anne-Kathrin1, Author
Rudelius, Martina1, Author
Deuschle, Friedrich-Christian1, Author
Keller, Ulrich1, Author
Lemeer, Simone1, Author
Verbeek, Mareike1, Author
Gotze, Katharina S.1, Author
Skerra, Arne1, Author
Weber, Wolfgang A.1, Author
Buchner, Johannes1, Author
Schulman, Brenda A.2, Author              
Kuster, Bernhard1, Author
Fernandez-Saiz, Vanesa1, AuthorBassermann, Florian1, Author more..
Affiliations:
1external, ou_persistent22              
2Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society, ou_2466699              

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Free keywords: Biochemistry & Molecular Biology; Cell Biology;
 Abstract: The complex architecture of transmembrane proteins requires quality control (QC) of folding, membrane positioning, and trafficking as prerequisites for cellular homeostasis and intercellular communication. However, it has remained unclear whether transmembrane protein-specific QC hubs exist. Here we identify cereblon (CRBN), the target of immunomodulatory drugs (IMiDs), as a co-chaperone that specifically determines chaperone activity of HSP90 toward transmembrane proteins by means of counteracting AHA1. This function is abrogated by IMiDs, which disrupt the interaction of CRBN with HSP90. Among the multiple transmembrane protein clients of CRBN-AHA1-HSP90 revealed by cell surface proteomics, we identify the amino acid transporter LAT1/CD98hc as a determinant of IMiD activity in multiple myeloma (MM) and present an Anticalin-based CD98hc radiopharmaceutical for MM radio-theranostics. These data establish the CRBNAHA1-HSP90 axis in the biogenesis of transmembrane proteins, link IMiD activity to tumor metabolism, and nominate CD98hc and LAT1 as attractive diagnostic and therapeutic targets in MM.

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Language(s): eng - English
 Dates: 2021
 Publication Status: Published in print
 Pages: 28
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Title: Molecular Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: - Volume / Issue: 81 (6) Sequence Number: - Start / End Page: 1170 - 1186.e10 Identifier: ISSN: 1097-2765
CoNE: https://pure.mpg.de/cone/journals/resource/954925610929