The spliceosome component Usp39 controls B cell development by regulating immunoglobulin gene rearrangement

Cell Rep. 2022 Feb 8;38(6):110338. doi: 10.1016/j.celrep.2022.110338.

Abstract

The spliceosome is a large ribonucleoprotein complex responsible for pre-mRNA splicing and genome stability maintenance. Disruption of the spliceosome activity may lead to developmental disorders and tumorigenesis. However, the physiological role that the spliceosome plays in B cell development and function is still poorly defined. Here, we demonstrate that ubiquitin-specific peptidase 39 (Usp39), a spliceosome component of the U4/U6.U5 tri-snRNP complex, is essential for B cell development. Ablation of Usp39 in B cell lineage blocks pre-pro-B to pro-B cell transition in the bone marrow, leading to a profound reduction of mature B cells in the periphery. We show that Usp39 specifically regulates immunoglobulin gene rearrangement in a spliceosome-dependent manner, which involves modulating chromatin interactions at the Igh locus. Moreover, our results indicate that Usp39 deletion reduces the pre-malignant B cells in Eμ-Myc transgenic mice and significantly improves their survival.

Keywords: B cell development; Usp39; chromatin interaction; immunoglobulin gene rearrangement; lymphoma; spliceosome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology*
  • Genes, Immunoglobulin / genetics*
  • Humans
  • Mice
  • RNA Precursors / metabolism*
  • Ribonucleoprotein, U4-U6 Small Nuclear / genetics
  • Ribonucleoprotein, U5 Small Nuclear / metabolism
  • Spliceosomes / metabolism*
  • Ubiquitin-Specific Proteases / genetics*
  • Ubiquitin-Specific Proteases / metabolism

Substances

  • RNA Precursors
  • Ribonucleoprotein, U4-U6 Small Nuclear
  • Ribonucleoprotein, U5 Small Nuclear
  • USP39 protein, human
  • Ubiquitin-Specific Proteases