A Ubiquitin-Independent Function of CRBN Mediates the Response to IMiDs

Immunomodulatory drugs (IMiD) such as lenalidomide are used to treat hematologic malignances including multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). IMiDs have been shown to primarily target CRBN, a substrate receptor for the CRL4 ubiquitin ligase complex, and promote ubiquitination and proteasomal degradation of CRBN substrates such as IKZF1 and IKZF3. Eichner and colleagues performed tandem-affinity purification to find additional CRBN substrates and identified CD147 and MCT1, which form a transmembrane complex involved in lactate transport, angiogenesis, proliferation, and invasion. CRBN expression increased the abundance of both proteins, indicating it is not a typical ubiquitin ligase–substrate interaction. Lenalidomide treatment destabilized the interaction between CD147 and MCT1, and competed with CD147 and MCT1 for CRBN binding, suggesting that CRBN normally stabilizes the CD147–MCT1 complex. However, the CD147–MCT1 stabilizing effect of CRBN was independent of ubiquitin and CRL4, pointing to a ubiquitin-independent function of CRBN. Indeed, CRBN was required for CD147 and MCT1 maturation and promoted the assembly and membrane localization of the CD147–MCT1 complex, further supporting a ubiquitin-independent chaperone-like function of CRBN. In MM cell lines, destabilization of the CD147–MCT1 complex was observed in lenalidomide-sensitive, but not lenalidomide-resistant, cells, suggesting that CD147–MCT1 destabilization may predict the response to IMiD. Overexpression of CD147 and MCT1 reduced the effects of lenalidomide in lenalidomide-sensitive MM cells, and CD147 and MCT1–depleted cells exhibited reduced tumor growth in a mouse xenotransplantation model, supporting a role for the CD147–MCT1 complex in mediating the antitumor effects of IMiDs. Patients with del(5q) MDS tend to respond better to lenalidomide than patients with non-del(5q) MDS, and correspondingly had elevated surface expression of CD147. Altogether, these findings provide further insight into the antitumor activity of IMiDs and reveal a ubiquitin-independent chaperone function of CRBN in stabilizing the CD147–MCT1 complex to promote MM and MDS.

Eichner R, Heider M, Fernández-Sáiz V, van Bebber F, Garz AK, Lemeer S, et al. Immunomodulatory drugs disrupt the cereblon–CD147–MCT1 axis to exert antitumor activity and teratogenicity. Nat Med 2016 Jun 13 [Epub ahead of print].