A Novel Mechanism for the Autonomous Termination of Pre-B Cell Receptor Expression via Induction of Lysosome-Associated Protein Transmembrane 5

Kawano, Yoshiaki; Ouchida, Rika; Wang, Ji Yang; Yoshikawa, Seiji; Yamamoto, Mutsumi; Kitamura, Daisuke; Karasuyama, Hajime

doi:10.1128/mcb.00531-12

Cited by 18 publications

(15 citation statements)

References 47 publications

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“…Large pre-B cells proliferate readily due to IL-7R and autonomous pre-BCR signaling. As pre-B cells differentiate into immature and mature B cells, IL-7R and pre-BCR signaling is down-regulated, and survival is maintained by tonic BCR and B cell-activating factor (BAFF) receptor (BAFFR) signaling (6,10). However, IL-7R receptor expression was similar between WT and Hrd1 KO mice across all B cell populations including pro/pre-B, immature, and mature B cells (Fig.…”

Section: Loss Of Hrd1 Resulted In the Developmental Defect Of Mature mentioning

confidence: 99%

“…ther developing into resting small pre-B cells (10,41). It is possible that upstream signals are required for Hrd1 degradation of the -heavy chain, which might terminate in later B cell stages.…”

Section: Hrd1 Governs B Cell Developmentmentioning

confidence: 99%

“…Unlike mature BCR, which is expressed primarily on the cell surface, pre-BCR is primarily retained in the endoplasmic reticulum (ER) (9). It has been shown in cell lines that pre-BCR and BCR can be shuttled from the ER to the endolysosomal compartment for degradation (10,11). However, it is unclear whether degrada-tion of the pre-BCR or BCR within the ER has a physiological role in B cell development.…”

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confidence: 99%

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The endoplasmic reticulum–resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice

Yang

Kong

Zhang

et al. 2018

Journal of Biological Chemistry

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Humoral immunity involves multiple checkpoints that occur in B cell development, maturation, and activation. The pre-B-cell receptor (pre-BCR) is expressed following the productive recombination of the immunoglobulin heavy-chain gene, and sSignalsing through the pre-BCR are required for the differentiation of pre-B cells into immature B cells. However, the molecular mechanisms controlling the pre-BCR expression and signaling strength remain undefined. Herein, we probed the role of the endoplasmic reticulum-associated, stress-activated E3 ubiquitin ligase HMG-CoA reductase degradation 1 (Hrd1) in B cell differentiation. Using mice with a specific Hrd1 deletion in pro-B cells and subsequent B cell developmental stages, we showed that the E3 ubiquitin ligase Hrd1 governs a critical checkpoint during B cell development. We observed that Hrd1 is required for degradation of the pre-BCR complex during the early stage of B cell development. As a consequence, loss of Hrd1 in the B cell lineage resulted in increased pre-BCR expression levels and a developmental defect in the transition from large to small pre-B cells. This defect, in turn, resulted in reduced fewer mature B cells in bone marrow and peripheral lymphoid organs. Our results revealed a novel critical role of Hrd1 in controlling a critical checkpoint in B cell-mediated immunity and suggest that Hrd1 may functioning as an E3 ubiquitin ligase of the pre-BCR complex.

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Section: Loss Of Hrd1 Resulted In the Developmental Defect Of Mature mentioning

confidence: 99%

Section: Hrd1 Governs B Cell Developmentmentioning

confidence: 99%

mentioning

confidence: 99%

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The endoplasmic reticulum–resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice

Yang

Kong

Zhang

et al. 2018

Journal of Biological Chemistry

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“…These observations raise the possibility that LAPTM5 promotes the lysosomal translocation of CD3ζ during its own trafficking from the Golgi to lysosomes. Recently, LAPTM5 has been suggested to transport the μH chain in the pre‐BCR complex from the ER to lysosomes 32 . It remains to be determined whether the pre‐BCR is transported to the Golgi before being sorted to lysosomes.…”

Section: Discussionmentioning

confidence: 99%

LAPTM5 promotes lysosomal degradation of intracellular CD3ζ but not of cell surface CD3ζ

et al. 2014

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The lysosomal protein LAPTM5 has been shown to negatively regulate cell surface T cell receptor (TCR) expression and T-cell activation by promoting CD3f degradation in lysosomes, but the mechanism remains largely unknown. Here we show that LAPTM5 promotes lysosomal translocation of intracellular CD3f but not of the cell surface CD3f associated with the mature TCR complex. Kinetic analysis of the subcellular localization of the newly synthesized CD3f suggests that LAPTM5 targets CD3f in the Golgi apparatus and promotes its lysosomal translocation. Consistently, a Golgi-localizing mutant CD3f can be transported to and degraded in the lysosome by LAPTM5. A CD3f YF mutant in which all six tyrosine residues in the immunoreceptor tyrosine-based activation motif are mutated to phenylalanines is degraded as efficiently as is wild type CD3f, further suggesting that TCR signaling-triggered tyrosine phosphorylation of CD3f is dispensable for LAPTM5-mediated degradation. Previously, Src-like adapter protein (SLAP) and E3 ubiquitin ligase c-Cbl have been shown to mediate the ubiquitination of CD3f in the internalized TCR complex and its subsequent lysosomal degradation. We show that LAPTM5 and SLAP/c-Cbl function in distinct genetic pathways to negatively regulate TCR expression. Collectively, these results suggest that CD3f can be degraded by two pathways: SLAP/c-Cbl, which targets internalized cell surface CD3f dependent on TCR signaling, and LAPTM5, which targets intracellular CD3f independent of TCR signaling.

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“…In addition, the LAPTM5 deficiency in pre-B cells led to the augmented expression level of surface pre-BCR. Pre-B cells in LAPTM5-deficient mice showed augmented pre-BCR expression levels, illustrating the importance of LAPTM5 in the autonomous downmodulation Biochem Genet (2015) 53:200-210 201 of the pre-BCR (Kawano et al 2012). LAPTM5 negatively regulated surface TCR expression and LAPTM5 deficiency could also result in elevated TCR expression on both CD4 ?…”

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confidence: 95%

Expression and Polymorphisms of Lysosome-Associated Protein Transmembrane 5 (LAPTM5) in Patients with Systemic Lupus Erythematosus in a Chinese Population

et al. 2015

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Lysosome-associated protein transmembrane 5 (LAPTM5) have been demonstrated a role in the prevention of lymphocyte hyperactivation, and its deficiency is involved in the immunological dysfunction of mouse models. The aim of this study was to detect mRNA expression of LAPTM5 in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE), and to assess association between LAPTM5 single nucleotide polymorphisms (SNPs) (rs10798801, rs4614309, rs1188348, and rs1188349) and SLE in a Chinese population. Real-time transcription-polymerase chain reaction analysis was used to determine expression of LAPTM5 mRNA in PBMCs from 132 patients with SLE and 62 healthy controls. LAPTM5 mRNA expression decreased in SLE patients (n = 71) compared with healthy controls (n = 58) (p = 3.68 × 10(-5)). The expression of LAPTM5 mRNA in SLE patients with lupus nephritis (LN) (n = 35) was lower than in those without LN (n = 36) (p = 0.004). The expression level of LAPTM5 correlated with serum total protein (r(s) = 0.41, p = 0.027) and negatively correlated with 24-h proteinuria (r(s) = -0.45, p = 0.027). LAPTM5 SNPs (rs10798801, rs4614309, rs1188348, and rs1188349) was also analyzed by restriction fragment length polymorphism (RFLP) in 380 SLE patients and 460 healthy controls. No significant difference in the genotype or allele frequencies for LAPTM5 SNPs was detected in 380 SLE patients and 460 healthy controls (p > 0.05). Substantially low frequency of GGAT haplotype was observed in SLE patients (p < 0.001). It is concluded that insufficient expression of LAPTM5 may take part in the pathogenesis of SLE and contribute to the severity of the disease, and none of LAPTM5 polymorphisms contributes significantly to SLE susceptibility in a Chinese population.

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A Novel Mechanism for the Autonomous Termination of Pre-B Cell Receptor Expression via Induction of Lysosome-Associated Protein Transmembrane 5

Cited by 18 publications

References 47 publications

The endoplasmic reticulum–resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice

The endoplasmic reticulum–resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice

LAPTM5 promotes lysosomal degradation of intracellular CD3ζ but not of cell surface CD3ζ

Expression and Polymorphisms of Lysosome-Associated Protein Transmembrane 5 (LAPTM5) in Patients with Systemic Lupus Erythematosus in a Chinese Population

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