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The Sel1L-Hrd1 endoplasmic reticulum-associated degradation complex manages a key checkpoint in B cell development #MMPMID27568564
Ji Y; Kim H; Yang L; Sha H; Roman CA; Long Q; Qi L
Cell Rep 2016[Sep]; 16 (10): 2630-40 PMID27568564show ga
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 the 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.