The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity

Xu, Yuanming; Zhao, Fang; Qiu, Quan; Chen, Kun; Wei, Juncheng; Kong, Qingfei; Gao, Beixue; Melo‐Cardenas, Johanna; Zhang, Bin; Zhang, Jinping; Song, Jianxun; Zhang, Donna D.; Zhang, Jianing; Fan, Yunping; Li, Hua-Bin; Fang, Deyu

doi:10.1038/ncomms12073

Cited by 51 publications

(54 citation statements)

References 48 publications

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

Section: Methodsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Wei

Chen

et al. 2018

The EMBO Journal

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The endoplasmic reticulum‐associated protein degradation (ERAD) is responsible for recognizing and retro‐translocating protein substrates, misfolded or not, from the ER for cytosolic proteasomal degradation. HMG‐CoA Reductase (HMGCR) Degradation protein—HRD1—was initially identified as an E3 ligase critical for ERAD. However, its physiological functions remain largely undefined. Herein, we discovered that hepatic HRD1 expression is induced in the postprandial condition upon mouse refeeding. Mice with liver‐specific HRD1 deletion failed to repress FGF21 production in serum and liver even in the refeeding condition and phenocopy the FGF21 gain‐of‐function mice showing growth retardation, female infertility, and diurnal circadian behavior disruption. HRD1‐ERAD facilitates the degradation of the liver‐specific ER‐tethered transcription factor CREBH to downregulate FGF21 expression. HRD1‐ERAD catalyzes polyubiquitin conjugation onto CREBH at lysine 294 for its proteasomal degradation, bridging a multi‐organ crosstalk in regulating growth, circadian behavior, and female fertility through regulating the CREBH‐FGF21 regulatory axis.

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

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wei

Chen

et al. 2018

The EMBO Journal

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“…In Gimap5 null hosts, which have spontaneous apoptosis in T cells, knocking down of CHOP inhibited T cell apoptosis [45]. In addition, a recent study revealed that deletion of Hrd1, an E3 ligase involved in UPR-induced ERAD, led to reduced T cell numbers and attenuated T cell polarization into Th1, Th2 and Th17 [46]. Therefore, moderate UPR promoted T cell function, whereas overwhelming UPR signaling will lead to impaired T cell responses and cell death.…”

Section: The Role Of Upr In T Cells Under Physiological and Pathologimentioning

confidence: 99%

“…Increased XBP-1 splicing, but not PERK or ATF6 activation, along with high expression of BiP and CHOP were found in acute necrotizing enterocolitis (A-NEC) patients who also had lower Th17 and Treg numbers [47]. In the experimental autoimmune encephalomyelitis (EAE) model, downregulating UPR via weakening ERAD leads to low disease progress, indicating that targeting UPR pathways may be a promising therapeutic option for multiple sclerosis [46]. Currently, whether UPR regulates T cell viability and function in the TME remains mostly elusive.…”

Section: The Role Of Upr In T Cells Under Physiological and Pathologimentioning

confidence: 99%

Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: a promising opportunity for cancer immunotherapy

Mohamed

Cao

Rodríguez

2017

Cancer Immunol Immunother

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The endoplasmic reticulum (ER) stress is a cellular process that occurs as a consequence of several stress circumstances, such as the accumulation of unfolded proteins in the lumen of the ER or distinct insults that disturb the ER normal function. Different conditions in the tumor microenvironment (TME), including hypoxia, nutrient deprivation, and the elevated production of reactive oxygen and nitrogen species destabilize the loading and dispatching of the newly synthesized proteins, triggering ER stress in cancer cells and tumor-infiltrating leukocytes. In order to cope with TME-induced ER stress, tumor and stromal cells initiate an adaptive response process that aims to resolve ER stress and to restore cellular homeostasis, which is referred as the Unfolded Protein Responses (UPR). Paradoxically, the UPR can also induce cell death under severe and/or permanent ER stress. The UPR is started through three mediators, the activation of the inositol-requiring enzyme-1α (IRE-1α), the pancreatic ER kinase (PKR)-like ER kinase (PERK), and the activating transcription factor 6 (ATF6). In this minireview, we will discuss the pro and anti-tumorigenic role of the UPR in cancer cells. In addition, we will describe the effects of the TME-induced ER stress in the immunosuppressive activity of tumor-infiltrating myeloid cells. Also, we will review the results of emerging therapeutic interventions that target ER stress and the UPR mediators in cancer. We postulate that the inhibition of ER stress or the UPR-related elements could represent a significant approach to increase the efficacy of various forms of cancer immunotherapy.

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“…Mice have been backcrossed onto the C57/BL6 genetic background for 7 generations. T cell-specific Gcn5- null mice were generated by breeding Gcn5 floxed mice with Lck-Cre transgenic mice as reported (23). Gcn5 loxp/loxp UB/ESR-Cre TG mice were generated by breeding Gcn5 floxed mice with UB / ESR-Cre transgenic mice.…”

Section: Methodsmentioning

confidence: 99%

The Histone Acetyltransferase Gcn5 Positively Regulates T Cell Activation

Gao¹,

Kong²,

Zhang³

et al. 2017

The Journal of Immunology

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Histone acetyltransferases (HATs) regulate inducible transcription in multiple cellular processes and during inflammatory and immune response. However, the functions of Gcn5 (general control nonrepressed-protein 5), an evolutionarily conserved HAT from yeast to human, in immune regulation remain unappreciated. Here we conditionally deleted Gcn5 (encoded by the Kat2a gene) specifically in T lymphocytes by crossing floxed Gcn5 and Lck-Cre mice and demonstrated that Gcn5 plays important roles in multiple stages of T cell functions including development, clonal expansion and differentiation. Loss of Gcn5 functions impaired T cell proliferation, IL-2 production and Th1/Th17, but not Th2 and Treg differentiation. Gcn5 is recruited onto the il-2 promoter by interacting with the nuclear factor of activated T cells (NFAT) in T cells upon TCR stimulation. Interestingly, instead of directly acetylating NFAT, Gcn5 catalyzes histone H3 lysine H9 (H3K9) acetylation to promote IL-2 production. T cell-specific suppression of Gcn5 partially protected mice from myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), an experimental model for human multiple sclerosis. Our study reveals previously unknown physiological functions for Gcn5 and a molecular mechanism underlying these functions in regulating T cell immunity. Hence, Gcn5 may be an important new target for autoimmune disease therapy.

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The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity

Cited by 51 publications

References 48 publications

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

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

Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: a promising opportunity for cancer immunotherapy

The Histone Acetyltransferase Gcn5 Positively Regulates T Cell Activation

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