Proteomics

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The IMiD receptor CRBN determines quality control of transmembrane proteins


ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos, LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell

DISEASE(S): Multiple Myeloma

SUBMITTER: Jana Zecha  

LAB HEAD: Bernhard Kuster

PROVIDER: PXD018244 | Pride | 2021-02-18

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
00673_A01_P005065_B00A_A00_R1.raw Raw
00673_A02_P005065_B00I_A00_R1.raw Raw
00673_A03_P005066_B00E_A00_R1.raw Raw
00673_A04_P005067_B00A_A00_R1.raw Raw
00673_A05_P005067_B00I_A00_R1.raw Raw
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Publications


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 counteract  ...[more]

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