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

Yi Yang, Sinyi Kong, Yana Zhang, Johanna Melo-Cardenas, Beixue Gao, Yusi Zhang, Donna Zhang, Bin Zhang, Jianxun Song, Edward Thorp, Kezhong Zhang, Jinping Zhang, Deyu Fang

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)12934-12944
Number of pages11
JournalJournal of Biological Chemistry
Volume293
Issue number33
DOIs
StatePublished - Jan 1 2018

Fingerprint

Hydroxymethylglutaryl CoA Reductases
Ubiquitin-Protein Ligases
B-Lymphocytes
Cells
Degradation
Cell Differentiation
Immunoglobulin Heavy Chain Genes
B-Lymphoid Precursor Cells
Immunoglobulin Heavy Chains
Defects
Cell Lineage
Humoral Immunity
Genetic Recombination
Bone Marrow
Bone
Genes
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

The endoplasmic reticulum–resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice. / Yang, Yi; Kong, Sinyi; Zhang, Yana; Melo-Cardenas, Johanna; Gao, Beixue; Zhang, Yusi; Zhang, Donna; Zhang, Bin; Song, Jianxun; Thorp, Edward; Zhang, Kezhong; Zhang, Jinping; Fang, Deyu.

In: Journal of Biological Chemistry, Vol. 293, No. 33, 01.01.2018, p. 12934-12944.

Research output: Contribution to journalArticle

Yang, Y, Kong, S, Zhang, Y, Melo-Cardenas, J, Gao, B, Zhang, Y, Zhang, D, Zhang, B, Song, J, Thorp, E, Zhang, K, Zhang, J & Fang, D 2018, 'The endoplasmic reticulum–resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice', Journal of Biological Chemistry, vol. 293, no. 33, pp. 12934-12944. https://doi.org/10.1074/jbc.RA118.002404
Yang, Yi ; Kong, Sinyi ; Zhang, Yana ; Melo-Cardenas, Johanna ; Gao, Beixue ; Zhang, Yusi ; Zhang, Donna ; Zhang, Bin ; Song, Jianxun ; Thorp, Edward ; Zhang, Kezhong ; Zhang, Jinping ; Fang, Deyu. / The endoplasmic reticulum–resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 33. pp. 12934-12944.
@article{31bc7ed84a4d4a3cafede097c2be92cc,
title = "The endoplasmic reticulum–resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice",
abstract = "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.",
author = "Yi Yang and Sinyi Kong and Yana Zhang and Johanna Melo-Cardenas and Beixue Gao and Yusi Zhang and Donna Zhang and Bin Zhang and Jianxun Song and Edward Thorp and Kezhong Zhang and Jinping Zhang and Deyu Fang",
year = "2018",
month = "1",
day = "1",
doi = "10.1074/jbc.RA118.002404",
language = "English (US)",
volume = "293",
pages = "12934--12944",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "33",

}

TY - JOUR

T1 - The endoplasmic reticulum–resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice

AU - Yang, Yi

AU - Kong, Sinyi

AU - Zhang, Yana

AU - Melo-Cardenas, Johanna

AU - Gao, Beixue

AU - Zhang, Yusi

AU - Zhang, Donna

AU - Zhang, Bin

AU - Song, Jianxun

AU - Thorp, Edward

AU - Zhang, Kezhong

AU - Zhang, Jinping

AU - Fang, Deyu

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85051752396&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85051752396&partnerID=8YFLogxK

U2 - 10.1074/jbc.RA118.002404

DO - 10.1074/jbc.RA118.002404

M3 - Article

C2 - 29907570

AN - SCOPUS:85051752396

VL - 293

SP - 12934

EP - 12944

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 33

ER -