Hrd1-mediated BLIMP-1 ubiquitination promotes dendritic cell MHCII expression for CD4 T cell priming during inflammation

Yang, Hee‐Young; Qiu, Quan; Gao, Beixue; Kong, Sinyi; Lin, Zhenghong; Fang, Deyu

doi:10.1084/jem.20140283

Cited by 74 publications

(80 citation statements)

References 58 publications

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“…Recently, Blimp-1 was shown to be ubiquitinated by a ubiquitin ligase, Hrd1, in dendritic cells. 31 The precise ubiquitination sites on Blimp-1 and whether Hrd1 is also involved in Blimp-1 ubiquitination and degradation in MM cells await further studies. Although we here show that downregulation of Aiolos and Ikaros by CUL4A is important for the anti-MM effects of lenalidomide, we could not exclude the possibility that other targets of CUL4 may also have a role in this context.…”

Section: 13mentioning

confidence: 99%

Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells

Hung

Chen

et al. 2016

Cell Death Differ

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The transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp-1) has crucial roles in the control of plasma cell differentiation and in maintaining survival of plasma cells. However, how Blimp-1 ensures the survival of plasma cell malignancy, multiple myeloma (MM), has remained elusive. Here we identified Aiolos, an anti-apoptotic transcription factor of MM cells, as a Blimp-1-interacting protein by mass spectrometry. ChIP coupled with DNA microarray was used to profile the global binding of Aiolos and Blimp-1 to endogenous targets in MM cells, which revealed their co-binding to a large number of genes, including apoptosis-related genes. Accordingly, Blimp-1 and Aiolos regulate similar transcriptomes in MM cells. Analysis of the binding motifs for Blimp-1 and Aiolos uncovered a partial motif that was similar across sites for both proteins. Aiolos promotes the binding of Blimp-1 to target genes and thereby enhances Blimp-1-dependent transcriptional repression. Furthermore, treatment with an anti-MM agent, lenalidomide, caused ubiquitination and proteasomal degradation of Blimp-1, leading to the de-repression of a new Blimp-1 direct target, CULLIN 4A (CUL4A), and reduced Aiolos levels. Accordingly, lenalidomide-induced cell death was partially rescued by reintroduction of Blimp-1 or knockdown of CUL4A. Thus, we demonstrated the functional impacts and underlying mechanisms of the interaction between Aiolos and Blimp-1 in maintaining MM cell survival. We also showed that interruption of Blimp-1/Aiolos regulatory pathways contributes to lenalidomide-mediated anti-MM activity.

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Section: 13mentioning

confidence: 99%

Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells

Hung

Chen

et al. 2016

Cell Death Differ

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“…During ERAD, misfolded proteins within the ER bind to chaperones such as BiP and are retrotranslocated into the cytosol to be ubiquitinated by the cytosolic RING (really interesting new gene) domain of Hrd1 (19). Whereas Hrd1 is required for the clearance of misfolded proteins during ERAD, emerging evidence suggests that Hrd1 can also regulate cellular functions by controlling the availability of specific proteins, such as Nrf2, Blimp1, and PGC-1β (21)(22)(23). In this paper, we report that Hrd1 plays a crucial role at the B-cell survival checkpoint by degrading the death receptor Fas during peripheral B-cell activation to downmodulate AICD.…”

mentioning

confidence: 99%

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.

Self Cite

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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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“…We found that miR-125b was lower in B cells from CD40 teasomal inhibitor MG132, indicating that CD40 signaling may engage this pathway to control BLIMP-1 at the protein level. It has been shown recently that BLIMP-1 in dendritic cells is targeted for ubiquitination and proteasomal degradation by the ERresident protein HRD1, leading to enhanced MHC-II expression and T cell priming (18). HRD1 is also involved in the ubiquitination and degradation of misfolded proteins, unassembled secretory IgM H chains (20,(26)(27)(28), and IRE-1a, which is induced when unfolded proteins accumulate after sustained ER stress that accompanies the classical UPR in PCs, where it splices XBP-1, which has several downstream functions in secreting cells (29).…”

Section: Discussionmentioning

confidence: 99%

“…5D). Further, when WT B cells were treated with the proteasomal inhibitor MG132, IRE-1a and BLIMP-1 amounts increased (Fig 5E), indicating that targeting of these proteins for proteasomal degradation via HRD1-mediated ubiquitination was involved (18,20). Thus, constitutive CD40 signaling in naive B cells reduces cellular Blimp-1 amounts by targeting both transcript and protein via independent pathways.…”

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

confidence: 93%

“…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%

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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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Hrd1-mediated BLIMP-1 ubiquitination promotes dendritic cell MHCII expression for CD4 T cell priming during inflammation

Cited by 74 publications

References 58 publications

Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells

Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells

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

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

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