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

Summary 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 CRBN-AHA1-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.

Graphical abstract

Highlights • CRBN functions as a transmembrane protein-specific co-chaperone of HSP90 • Disruption of CRBN-HSP90 interaction determines the anti-tumor activity of IMiDs • The CD98hc/LAT1 complex is a central target of IMiDs in multiple myeloma • CD98hc-Anticalin is a theranostic tool in multiple myeloma

Heider et al. investigate the molecular function of immunomodulatory drugs (IMiDs) and describe their target, CRBN, as a transmembrane protein (TP)-specific co-chaperone of the HSP90-AHA1 axis. By disrupting CRBN-HSP90 interaction, IMiDs lead to destabilization of various TPs as CD98hc/LAT1, which serve as therapeutic targets in multiple myeloma.