The IMiD receptor CRBN determines quality control of transmembrane proteins

The complex architecture of transmembrane proteins requires quality control (QC) for folding and membrane positioning, a prerequisite for cellular homoeostasis and intercellular communication. However, it has remained unclear whether transmembrane proteins-specific QC hubs exist. Here we specify Cereblon (CRBN), the target of immunomodulatory drugs (IMiDs), as a co-chaperone that specifically determines chaperone activity of HSP90 towards transmembrane proteins by means of counteracting AHA1. This function is abrogated by IMiDs, which disrupt the interaction of CRBN with the closed conformation of HSP90. Cell surface proteomics identifies different transmembrane protein clients of the CRBN-AHA1-HSP90 nexus. Among these, we characterize the amino acid transporters LAT1 and CD98hc as determinants of IMiD activity in multiple myeloma (MM) both in vitro and in vivo. These data establish the CRBN-AHA1-HSP90 axis in the biogenesis of transmembrane proteins, link IMiD activity to tumor metabolism, and specify CD98 as an attractive diagnostic and therapeutic target in multiple myeloma.