LAPTM5 mediates immature B cell apoptosis and B cell tolerance by regulating the WWP2-PTEN-AKT pathway

Proc Natl Acad Sci U S A. 2022 Sep 6;119(36):e2205629119. doi: 10.1073/pnas.2205629119. Epub 2022 Aug 29.


Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains poorly understood. We show that BCR stimulation up-regulates the expression of the lysosomal-associated transmembrane protein 5 (LAPTM5), which in turn triggers apoptosis of immature B cells through two pathways. LAPTM5 causes BCR internalization, resulting in decreased phosphorylation of SYK and ERK. In addition, LAPTM5 targets the E3 ubiquitin ligase WWP2 for lysosomal degradation, resulting in the accumulation of its substrate PTEN. Elevated PTEN levels suppress AKT phosphorylation, leading to increased FOXO1 expression and up-regulation of the cell cycle inhibitor p27Kip1 and the proapoptotic molecule BIM. In vivo, LAPTM5 is involved in the elimination of autoreactive B cells and its deficiency exacerbates autoantibody production. Our results reveal a previously unidentified mechanism that contributes to immature B cell apoptosis and B cell tolerance.

Keywords: B cell tolerance; E3 ubiquitin ligase; apoptosis; immature B cell; lysosomal-associated transmembrane protein 5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Forkhead Box Protein O1 / metabolism
  • Humans
  • Immune Tolerance*
  • Lysosomes / metabolism
  • Membrane Proteins* / genetics
  • PTEN Phosphohydrolase / metabolism
  • Precursor Cells, B-Lymphoid* / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Ubiquitin-Protein Ligases / metabolism


  • CDKN1B protein, human
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Membrane Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • LAPTM5 protein, human
  • WWP2 protein, human
  • Ubiquitin-Protein Ligases
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human