Synoviolin promotes IRE1 ubiquitination and degradation in synovial fibroblasts from mice with collagen‐induced arthritis

Gao, Beixue; Lee, Sang Myeong; Chen, An; Zhang, Jinping; Zhang, Donna D.; Kannan, K.; Ortmann, Robert A.; Fang, Deyu

doi:10.1038/embor.2008.37

Cited by 98 publications

(87 citation statements)

References 18 publications

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“…This conclusion is validated by the following observations: (i) Conditional deletion of Hrd1 specifically in B-cell lineage results in reduced mature B cells in the peripheral lymphoid organs; (ii) Hrd1-deficiency sensitizes Fas-mediated activation-induced B-cell death, which can be largely Hrd1 functions as a critical regulator in protecting B cells from AICD, based on our observation that apoptosis in Hrd1 KO peripheral B cells upon antigenic stimulation was significantly increased. Fas was up-regulated at both the mRNA and protein level, initially suggesting that Fas expression might be indirectly induced upon increase of Hrd1 substrates, such as p53 or IRE1α (27,30). However, we did not detect a significant increase in the p53-target genes PUMA and p21 in activated Hrd1 KO peripheral B cells compared with WT.…”

Section: Discussioncontrasting

confidence: 48%

“…S5 E and F), further confirming that Hrd1 protects B cells from AICD independent of UPR response. We have recently discovered that Hrd1 suppresses ER-stress-induced cell death through targeting the downstream ER-stress sensor IRE1α for ubiquitination and degradation (27,28). However, further deletion of IRE1α in Hrd1 KO mice could not rescue the reduction in the peripheral B cells in spleen (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Hrd1 has been shown to protect against ER-stressinduced apoptosis through destructing the misfolded proteins (26,27). To determine the contribution of UPR (unfolded protein response)-induced apoptosis in Hrd1 KO peripheral B cells, we examined the induction of ER-stress target genes.…”

Section: Resultsmentioning

confidence: 99%

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

Kong¹,

Yang²,

Xu³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussioncontrasting

confidence: 48%

Section: Resultsmentioning

confidence: 99%

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

Kong¹,

Yang²,

Xu³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…It also plays a crucial role in the pathogenesis of arthropathy and liver cirrhosis/fibrosis (Amano et al 2003;Hasegawa et al 2010). Although Hrd1 was initially characterized as an E3 ubiquitin ligase controlling ERassociated degradation (ERAD), recent reports demonstrate that Hrd1 can also control the turnover of non-ERAD substrates such as p53, IRE1, and Nrf1, a member of the cap'n'collar (CNC) transcription factor family (Yamasaki et al 2007;Gao et al 2008;Steffen et al 2010;Tsuchiya et al 2011). In addition to the UPR, reactive oxygen species (ROS) have been shown to play a major role in the pathogenesis of liver cirrhosis (Lotersztajn et al 2005;Wynn and Ramalingam 2012).…”

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confidence: 99%

Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis

et al. 2014

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Increased endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) are the salient features of end-stage liver diseases. Using liver tissues from liver cirrhosis patients, we observed up-regulation of the XBP1-Hrd1 arm of the ER stress response pathway and down-regulation of the Nrf2-mediated antioxidant response pathway. We further confirmed this negative regulation of Nrf2 by Hrd1 using Hrd1 conditional knockout mice. Downregulation of Nrf2 was a surprising result, since the high levels of ROS should have inactivated Keap1, the primary ubiquitin ligase regulating Nrf2 levels. Here, we identified Hrd1 as a novel E3 ubiquitin ligase responsible for compromised Nrf2 response during liver cirrhosis. In cirrhotic livers, activation of the XBP1-Hrd1 arm of ER stress transcriptionally up-regulated Hrd1, resulting in enhanced Nrf2 ubiquitylation and degradation and attenuation of the Nrf2 signaling pathway. Our study reveals not only the convergence of ER and oxidative stress response pathways but also the pathological importance of this cross-talk in liver cirrhosis. Finally, we showed the therapeutic importance of targeting Hrd1, rather than Keap1, to prevent Nrf2 loss and suppress liver cirrhosis.

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“…3B). It has been shown that the ERresident ubiquitin ligase Hrd1 targets BLIMP-1 for ubiquitination and degradation in dendritic cells (18) and also targets IRE-1a (18,19), and hence we examined whether this pathway could operate downstream of CD40 engagement in B cells. We found that Hrd1 transcripts were higher in WT B cells than in CD40 2/2 B cells, and that Hrd1 was induced when WT B cells were treated with anti-CD40 Ab for 24 h (Fig.…”

Section: Cd40 Ligation Induces Hrd1 That Targets Blimp-1 and Ire-1a Pmentioning

confidence: 99%

Constitutive CD40 Signaling Calibrates Differentiation Outcomes in Responding B Cells via Multiple Molecular Pathways

Basu

Kaw

D'Souza

et al. 2016

The Journal of Immunology

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CD40 signaling during B cell activation is known to inhibit terminal differentiation and promote memory generation. Blimp-1 is essential for efficient plasma cell (PC) generation, and although CD40 signaling is known to inhibit Blimp-1 induction during B cell activation, the mechanisms involved have been unclear. We report that CD40 signaling induces miR-125b that targets Blimp-1 transcripts, and increases amounts of the ubiquitin ligase Hrd1 that targets BLIMP-1 protein for proteasomal degradation. CD40 signaling also inhibits the early unfolded protein response (UPR) of activated B cells that precedes the induction of terminal differentiation, and Hrd1 feeds into this pathway by targeting the core UPR component IRE-1α. Strikingly, CD40 signaling in the absence of BCR- or TLR-ligation also repressed Blimp-1 transcripts, suggesting that noncognate ligation of CD40 via T–B interactions may repress Blimp-1 in vivo. In support of this, we find that naive B cells purified from CD40–CD154 interaction–deficient mice express higher amounts of Blimp-1 and lower amounts of microRNAs and Hrd1. Higher basal amounts of Blimp-1 in naive CD40−/− B cells correlate with an increased tendency of the cells to undergo terminal differentiation upon LPS stimulation. Conversely, a 24-h exposure to CD40 ligation during LPS stimulation of wild-type B cells is sufficient to inhibit PC generation. The data show that CD40-mediated inhibition of PC generation is via engagement of multiple pathways that involve repression of Blimp-1 and inhibition of the UPR that prepares cells to become professional secretors. They also show that constitutive CD40 signaling in vivo involving bystander T–B interactions can calibrate B cell differentiation outcomes.

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Synoviolin promotes IRE1 ubiquitination and degradation in synovial fibroblasts from mice with collagen‐induced arthritis

Cited by 98 publications

References 18 publications

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

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

Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis

Constitutive CD40 Signaling Calibrates Differentiation Outcomes in Responding B Cells via Multiple Molecular Pathways

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