title: The Sel1L-Hrd1 Endoplasmic Reticulum-Associated Degradation Complex Manages a Key Checkpoint in B Cell Development.
abstract: Endoplasmic reticulum (ER)-associated degradation (ERAD) is a principal mechanism that targets ER-associated proteins for cytosolic proteasomal degradation. Here, our data demonstrate a critical role for the Sel1L-Hrd1 complex, the most conserved branch of ERAD, in early B cell development. Loss of Sel1L-Hrd1 ERAD in B cell precursors leads to a severe developmental block at the transition from large to small pre-B cells. Mechanistically, we show that Sel1L-Hrd1 ERAD selectively recognizes and targets the pre-B cell receptor (pre-BCR) for proteasomal degradation in a BiP-dependent manner. The pre-BCR complex accumulates both intracellularly and at the cell surface in Sel1L-deficient pre-B cells, leading to persistent pre-BCR signaling and pre-B cell proliferation. This study thus implicates ERAD mediated by Sel1L-Hrd1 as a key regulator of B cell development and reveals the molecular mechanism underpinning the transient nature of pre-BCR signaling.
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors: Yewei
authors: Y
authors: Ji
authors: Graduate Field of Immunology and Infectious Disease, Cornell University, Ithaca, NY 14853, USA.
authors: Hana
authors: H
authors: Kim
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors: Liu
authors: L
authors: Yang
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors: Haibo
authors: H
authors: Sha
authors: Department of Cell Biology, College of Medicine and Program in Molecular and Cellular Biology, The School of Graduate Studies, State University of New York, Downstate Medical Center at Brooklyn, New York, NY 11203, USA.
authors: Christopher A
authors: CA
authors: Roman
authors: Laboratory Animal Research Center, Medical College of Soochow University, Suzhou 215006, Jiangsu, China.
authors: Qiaoming
authors: Q
authors: Long
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Graduate Field of Immunology and Infectious Disease, Cornell University, Ithaca, NY 14853, USA. Electronic address: lingq@med.umich.edu.
authors: Ling
authors: L
authors: Qi
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D002453:Cell Cycle; D059447:Cell Cycle Checkpoints; D048429:Cell Size; D060746:Endoplasmic Reticulum-Associated Degradation; D047908:Intracellular Signaling Peptides and Proteins; D008810:Mice, Inbred C57BL; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell; D013379:Substrate Specificity; D051742:Transcription Factor CHOP / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D018941:Antigens, CD19; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011947:Receptors, Antigen, B-Cell; C492169:Sel1h protein, mouse; D051742:Transcription Factor CHOP; C498235:Syvn1 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: B cell development; Hrd1; Sel1L; endoplasmic reticulum-associated degradation; large pre-B cells; pre-B cell receptor