A Novel Mechanism for the Autonomous Termination of Pre-B Cell Receptor Expression via Induction of Lysosome-Associated Protein Transmembrane 5
A Novel Mechanism for the Autonomous Termination of Pre-B Cell Receptor Expression via Induction of Lysosome-Associated Protein Transmembrane 5
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DOI：
10.1128/mcb.00531-12
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发表时间：
2012-11-01
影响因子：
5.3
通讯作者：
Karasuyama, Hajime
中科院分区：
文献类型：
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作者：
Kawano, Yohei;Ouchida, Rika;Karasuyama, Hajime
前B细胞受体(BCR)的表达仅限于B细胞发育的早期阶段，其失调与B细胞系的异常有关，包括白血病的发生。以前的研究表明，Pre-BCR信号可能在Pre-BCR基因表达沉默之前就触发了Pre-BCR表达的自主终止，从而阻止了Pre-BCR的持续表达。然而，潜在的机制仍然定义不清。在这里，我们证明了Pre-BCR信号诱导溶酶体相关蛋白跨膜5(LAPTM5)的表达，从而导致Pre-BCR的迅速下调。虽然LAPTM5诱导对细胞表面前BCR的内化没有显著影响，但它诱导了大量细胞内前BCR从内质网移位到溶酶体室，同时细胞内前BCR蛋白水平急剧下降。这种还原被溶酶体抑制剂抑制，表明溶酶体对前BCR的降解。值得注意的是，Pre-B细胞中LAPTM5缺陷导致了表面Pre-BCR表达水平的增强。总的来说，Pre-BCR通过诱导LAPTM5诱导其自身表达的迅速下调，从而促进细胞内Pre-BCR池的溶酶体运输和降解，从而限制Pre-BCR向细胞表面的供应。
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 down-modulation 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.