Midnolin stimulates proteasome activity necessary for lymphopoiesis and B cell cancer growth

ABSTRACT: We identified the essential gene encoding midnolin in a genetic screen in which multiple Midn alleles caused reductions in peripheral B cells and T cell-independent antibody responses. Causation was confirmed in mice with targeted deletion of 4 of 6 MIDN protein isoforms. MIDN augmented proteasome activity in lymphocytes but few other cell types. By cryo-electron microscopy we showed that MIDN binds directly to the 26S proteasome. MIDN-deficient B cells displayed aberrant activation of the IRE-1/XBP-1 pathway of the unfolded protein response. Partial or complete MIDN deficiency suppressed B lymphoproliferation in three models of B cell malignancies. Thus, MIDN is required for proteasome activity in support of lymphopoiesis and malignant B cell proliferation over a broad range of differentiation states. Targeting MIDN in B cell malignancies may avoid off-tumor toxicities caused by proteasome inhibition throughout the body.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Bruce Beutler  

PROVIDER: MSV000093397 | MassIVE | Tue Nov 14 06:56:00 GMT 2023

SECONDARY ACCESSION(S): PXD046953

REPOSITORIES: MassIVE