Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas

Abstract

Humoral immunity involves multiple checkpoints during B-cell development, maturation, and activation. The cell death receptor CD95/Fas-mediated apoptosis plays a critical role in eliminating the unwanted activation of B cells by self-reactive antigens and in maintaining B-cell homeostasis through activation-induced B-cell death (AICD). The molecular mechanisms controlling AICD remain largely undefined. Herein, we show that the E3 ubiquitin ligase Hrd1 protected B cells from activation-induced cell death by degrading the death receptor Fas. Hrd1-null B cells exhibited high Fas expression during activation and rapidly underwent Fas-mediated apoptosis, which could be largely inhibited by FasL neutralization. Fas mutation in Hrd1 KO mice abrogated the increase in B-cell AICD. We identified Hrd1 as the first E3 ubiquitin ligase of the death receptor Fas and Hrd1-mediated Fas destruction as a molecular mechanism in regulating B-cell immunity.Hrd1 | Fas | B cells | ubiquitination B -cell immunity involves several checkpoints, which are important to orchestrate and balance survival and apoptotic signals and control the quality and size of the B-cell compartment (1, 2). The earliest steps in B-cell development occur in the bone marrow, where assembly of the pre-B-cell receptor (pre-BCR) followed by the mature BCR occurs in distinct stages. Once the mature BCR is expressed, B lymphocytes then progress into the immature B-cell stage, where further selection checkpoints occur before the immature B cells transition to the periphery and mature into circulating B cells (2, 3). Mature B cells are maintained through tonic BCR, CD40, and B-cell-activating factor receptor (BAFFR) signaling (4). Activation by cross-linking the BCR leads to rapid proliferation, somatic hypermutation, and further differentiation of B cells (5, 6). The expansion of activated B-cell compartment is subsequently downmodulated through activation-induced cell death (AICD) (7,8).The death receptor Fas has been identified as a key regulator of AICD of B cells (9-11). Fas is highly expressed on activated B cells, particularly in the germinal center, where it mediates the deletion of autoreactive or unproductive somatic hypermutated B cells (12)(13)(14). Fas, as well as its ligand FasL, play critical roles in B-cell apoptosis. The selective removal of Fas from activated B cells results in lupus-like disease and autoantibody production (15-17). It has been a widely accepted view that the Fas/FasL mutations result in, at least in part, a failure to eliminate self-reactive GC B cells in autoimmune patients and animal models (12, 18). However, more recent studies show that FAS is in fact not required for the elimination of self-reactive GC B cells. Instead, Fas inactivation led to accumulation of a population of unconventional GC B cells that underwent somatic hypermutation and survived despite losing antigen reactivity (8). Nevertheless, it is clear that Fasmediated B-cell death is critically involved in B-cell-mediated autoimmune diseases. However, the molecular...

HRD1‐ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination

“…HRD1 floxed mice were used as previously described (Kong et al , ; Xu et al , ; Yang et al , ). Albumin‐Cre (catalogue no.…”

“…The IRE1α downstream transcription factor Xbp‐1 has been shown to regulate HRD1 mRNA transcription, providing an interesting feedback loop for HRD1‐IRE1α during ER stress response (Gao et al , ). We recently found that HRD1 is involved in immune regulation in dendritic cell antigen presentation, as well as in the activation of both T and B lymphocytes (Kong et al , ; Xu et al , ; Yang et al , ). However, it is not clear whether HRD1 is regulated upon metabolic stresses.…”

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

“…Based on our findings, it is likely that the reduced mature B cell number in Hrd1 KO bone marrow is due to defective pre-BCR down-regulation in the pre-B cell population, which results in reduced mature BCR expression and signaling that is required for mature B cell survival. In fact, we have recently discovered that Hrd1 regulates activation-induced B cell death through targeting the death receptor Fas (36). Therefore, Hrd1 appears to be critical to regulate B cell functions at multiple distinct stages.…”

Hepatic Sel1L‐Hrd1 ER‐associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH

“…Subsequent characterization of cell type‐specific Sel1L‐knockout (Ji et al , ; Sha et al , ; Shi et al , ; Sun et al , , , ) and Hrd1‐knockout (Fujita et al , ; Kong et al , ; Wu et al , ; Xu et al , ; Yang et al , ) mouse models, including gene deletion in adipocytes, immune cells, enterocytes, and various neurons, has revealed the significance of Sel1L‐Hrd1 ERAD in a cell type‐ and substrate‐specific manner in vivo (Qi et al , ). For example, mice with Sel1L deficiency in adipocytes exhibit lipodystrophy and postprandial hyperlipidemia due to the ER retention of lipoprotein lipase (LPL) (Sha et al , ).…”