UBXN3B Is Crucial for B Lymphopoiesis

Hematopoiesis is finely regulated to enable timely production of the right numbers and types of immune cells. Herein, we report the crucial function of UBXN3B in B lymphopoiesis. In the inducible global knockout and B cell-specific Ubxn3b knockout model, the terminal B cell number is reduced by > 90% in both Ubxn3b-/- mouse models. Transfer of wildtype bone marrows to irradiated global Ubxn3b-/- restores the B population, while reverse transplantation fails to do so. The deficiency begins from the precursor stage. The B population drops rapidly with significant apoptosis, presents a much higher level of pro-caspase-3 protein following induction of Ubxn3b knockout. RNA-sequencing reveals significantly suppressed cell cycle genes while upregulated TP53 signaling in Ubxn3b-/- B cells. Ubxn3b-/- mice are highly vulnerable to respiratory viruses, with increased lung viral loads and immunopathology, reduced B population and virus-specific IgM/IgG. This study reveals a cell-intrinsic essential role of UBXN3B in B cell survival and UBXN3B as a potential therapeutic target for B-cell related diseases. To investigate the function of UBXN3b in B lymphopoiesis, we established an inducible global knockout mouse model. In this model, tamoxifen administration induces the knockout of Ubxn3b. Bone marrows from tamoxifen or oil treated mice were sorted for B subsets. Subsequent comparartive gene expression profilling analysis was conduted using RNA-seq data from mature B subset.