MassIVE MSV000093397

Partial Public PXD046953

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

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Description

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. [doi:10.25345/C59K4641F] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Midnolin, proteasome, lymphopoiesis, B cell cancer

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Principal Investigators:
(in alphabetical order) 		Bruce Beutler, UT Southwestern Medical Center, United States
Submitting User: JJMoresco
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