The Sel1L-Hrd1 Endoplasmic Reticulum-Associated Degradation Complex Manages a Key Checkpoint in B Cell Development

• Main Authors: Yewei Ji, Hana Kim, Liu Yang, Haibo Sha, Christopher A. Roman, Qiaoming Long, Ling Qi
• Format: Article
• Language: English
• Published: Elsevier 2016-09-01
• Series: Cell Reports
• Subjects: endoplasmic reticulum-associated degradation; Sel1L; Hrd1; B cell development; pre-B cell receptor; large pre-B cells
• Online Access: http://www.sciencedirect.com/science/article/pii/S221112471631035X

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.