title: A novel mechanism for the autonomous termination of pre-B cell receptor expression via induction of lysosome-associated protein transmembrane 5.
abstract: The expression of the pre-B cell receptor (BCR) is confined to the early stage of B cell development, and its dysregulation is associated with anomalies of B-lineage cells, including leukemogenesis. Previous studies suggested that the pre-BCR signal might trigger the autonomous termination of pre-BCR expression even before the silencing of pre-BCR gene expression to prevent sustained pre-BCR expression. However, the underlying mechanism remains ill defined. Here we demonstrate that the pre-BCR signal induces the expression of lysosome-associated protein transmembrane 5 (LAPTM5), which leads to the prompt downmodulation of the pre-BCR. While LAPTM5 induction had no significant impact on the internalization of cell surface pre-BCR, it elicited the translocation of a large pool of intracellular pre-BCR from the endoplasmic reticulum to the lysosomal compartment concomitantly with a drastic reduction of the level of intracellular pre-BCR proteins. This reduction was inhibited by lysosomal inhibitors, indicating the lysosomal degradation of the pre-BCR. Notably, the LAPTM5 deficiency in pre-B cells led to the augmented expression level of surface pre-BCR. Collectively, the pre-BCR induces the prompt downmodulation of its own expression through the induction of LAPTM5, which promotes the lysosomal transport and degradation of the intracellular pre-BCR pool and, hence, limits the supply of pre-BCR to the cell surface.
authors.affiliation: Department of Immune Regulation, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kawano
authors.forename: Rika
authors.initials: R
authors.lastname: Ouchida
authors.forename: Ji-Yang
authors.initials: JY
authors.lastname: Wang
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yoshikawa
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kitamura
authors.forename: Hajime
authors.initials: H
authors.lastname: Karasuyama
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000378:metabolism*; D008213:Lymphocyte Activation; D008247:Lysosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D054420:Pre-B Cell Receptors / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D017874:Immediate-Early Proteins; C484408:Laptm5 protein, mouse; D008565:Membrane Proteins; D054420:Pre-B Cell Receptors