Deficiency of the BiP cochaperone ERdj4 causes constitutive endoplasmic reticulum stress and metabolic defects

Fritz, Jill M.; Dong, Mei; Apsley, Karen S.; Martin, Emily P.; Na, Cheng-Lun; Sitaraman, Sneha; Weaver, Timothy E.

doi:10.1091/mbc.e13-06-0319

Cited by 53 publications

(56 citation statements)

References 59 publications

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“…Although ERdj4 is clearly required for ERAD of specific terminally misfolded proteins, emerging evidence suggests that it may also play a more general role in productive protein folding in highly metabolic cells. Mice deficient in ERdj4 exhibit constitutive ER stress associated with defects in growth, development and metabolism [17]. The current study extends these findings by demonstrating that hypomorphic expression of ERdj4 leads to alterations in hematopoiesis and lymphocyte function.…”

Section: Discussionsupporting

confidence: 77%

The BiP Cochaperone ERdj4 Is Required for B Cell Development and Function

Fritz

Weaver

2014

PLoS ONE

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ERdj4 is a BiP cochaperone regulated by the unfolded protein response to facilitate degradation of unfolded and/or misfolded proteins in the endoplasmic reticulum. As the unfolded protein response plays a critical role in B cell maturation and antibody production, ERdj4 gene trap mice were generated to determine if this chaperone was required for B cell homeostasis. Homozygosity for the trapped allele resulted in hypomorphic expression of ERdj4 in bone marrow cells and abnormal development of hematopoietic lineages in the bone marrow. The number of myeloid cells was increased, while the number of erythroid and B lymphoid cells was reduced in ERdj4 gene trap mice compared to controls. An intrinsic B cell defect was identified that decreased survival of B cell precursors including large and small pre-B, and immature B cells. Consistent with impaired B lymphopoiesis, the number of mature follicular B cells was reduced in both the bone marrow and spleen of ERdj4 gene trap mice. Paradoxically, unchallenged ERdj4 gene trap mice showed non-specific hypergammaglobulinemia and gene trap B cells exhibited increased proliferation, survival and isotype switching in response to LPS stimulation. Although ERdj4 gene trap mice responded normally to T cell-independent antigen, they failed to mount a specific antibody response to T cell-dependent antigen in vivo. Collectively, these findings demonstrate that the chaperone activity of ERdj4 is required for survival of B cell progenitors and normal antibody production.

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Section: Discussionsupporting

confidence: 77%

The BiP Cochaperone ERdj4 Is Required for B Cell Development and Function

Fritz

Weaver

2014

PLoS ONE

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“…This gene set contains factors involved in the ER stress response, consistent with an earlier study showing that some genes from this group (PERK, ATF3/4, ERO1α) are induced at the protein level in IBV-infected avian cells [23,45,46]. Our mRNA expression and bioinformatics analysis identified a large number of additional genes of the ER stress response that are induced by HCoV-229E, such as CHAC1, an enzyme that degrades glutathione [47,48] and others (FICD, HERPUD1, DNAJB9/ERDJ4) functioning as regulators of AMPylation, ubiquitylation or co-chaperones, respectively [49][50][51]. Moreover, HCoV-229E was found to upregulate transcription factors (TFs) with known functions such as EGR1 and c-JUN, but also poorly characterized TFs such as zinc finger (ZNF)165, basic helix-loop-helix-type transcription factors (BHLHE40/41) or zinc finger and BTB domain-containing 43 (ZBTB43) [52,53].…”

Section: Discussionmentioning

confidence: 87%

The NF-κB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells

et al. 2017

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Coronavirus replication takes place in the host cell cytoplasm and triggers inflammatory gene expression by poorly characterized mechanisms. To obtain more insight into the signals and molecular events that coordinate global host responses in the nucleus of coronavirus-infected cells, first, transcriptome dynamics was studied in human coronavirus 229E (HCoV-229E)-infected A549 and HuH7 cells, respectively, revealing a core signature of upregulated genes in these cells. Compared to treatment with the prototypical inflammatory cytokine interleukin(IL)-1, HCoV-229E replication was found to attenuate the inducible activity of the transcription factor (TF) NF-κB and to restrict the nuclear concentration of NF-κB subunits by (i) an unusual mechanism involving partial degradation of IKKβ, NEMO and IκBα and (ii) upregulation of TNFAIP3 (A20), although constitutive IKK activity and basal TNFAIP3 expression levels were shown to be required for efficient virus replication. Second, we characterized actively transcribed genomic regions and enhancers in HCoV-229E-infected cells and systematically correlated the genome-wide gene expression changes with the recruitment of Ser5-phosphorylated RNA polymerase II and prototypical histone modifications (H3K9ac, H3K36ac, H4K5ac, H3K27ac, H3K4me1). The data revealed that, in HCoV-infected (but not IL-1-treated) cells, an extensive set of genes was activated without inducible p65 NF-κB being recruited. Furthermore, both HCoV-229E replication and IL-1 were shown to upregulate a small set of genes encoding immunomodulatory factors that bind p65 at promoters and require IKKβ activity and p65 for expression. Also, HCoV-229E and IL-1 activated a common set of 440 p65-bound enhancers that differed from another 992 HCoV-229E-specific enhancer regions by distinct TF-binding motif combinations. Taken together, the study shows that cytoplasmic RNA viruses fine-tune NF-κB signaling at multiple levels and profoundly reprogram the host cellular chromatin landscape, thereby orchestrating the timely coordinated expression of genes involved in multiple signaling, immunoregulatory and metabolic processes.

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“…Following inflation fixation, lung slices were incubated with 2% lanthanum nitrate in fixative at room temperature overnight, followed by routine preparation for TEM4546. Electron micrographs were collected using a Hitachi H-7650 TEM (Hitachi High Technologies America, Inc., Dallas, TX) equipped with an AMT transmission electron microscope charge-coupled device camera (Advanced Microscopy Techniques, Woburn, MA).…”

Section: Methodsmentioning

confidence: 99%

The Phosphatidylcholine Transfer Protein Stard7 is Required for Mitochondrial and Epithelial Cell Homeostasis

Yang

Luo

et al. 2017

Sci Rep

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Mitochondria synthesize select phospholipids but lack the machinery for synthesis of the most abundant mitochondrial phospholipid, phosphatidylcholine (PC). Although the phospholipid transfer protein Stard7 promotes uptake of PC by mitochondria, the importance of this pathway for mitochondrial and cellular homeostasis represents a significant knowledge gap. Haploinsufficiency for Stard7 is associated with significant exacerbation of allergic airway disease in mice, including an increase in epithelial barrier permeability. To test the hypothesis that Stard7 deficiency leads to altered barrier structure/function downstream of mitochondrial dysfunction, Stard7 expression was knocked down in a bronchiolar epithelial cell line (BEAS-2B) and specifically deleted in lung epithelial cells of mice (Stard7epi∆/∆). Stard7 deficiency was associated with altered mitochondrial size and membrane organization both in vitro and in vivo. Altered mitochondrial structure was accompanied by disruption of mitochondrial homeostasis, including decreased aerobic respiration, increased oxidant stress, and mitochondrial DNA damage that, in turn, was linked to altered barrier integrity and function. Both mitochondrial and barrier defects were largely corrected by targeting Stard7 to mitochondria or treating epithelial cells with a mitochondrial-targeted antioxidant. These studies suggest that Stard7-mediated transfer of PC is crucial for mitochondrial homeostasis and that mitochondrial dysfunction contributes to altered barrier permeability in Stard7-deficient mice.

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Deficiency of the BiP cochaperone ERdj4 causes constitutive endoplasmic reticulum stress and metabolic defects

Cited by 53 publications

References 59 publications

The BiP Cochaperone ERdj4 Is Required for B Cell Development and Function

The BiP Cochaperone ERdj4 Is Required for B Cell Development and Function

The NF-κB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells

The Phosphatidylcholine Transfer Protein Stard7 is Required for Mitochondrial and Epithelial Cell Homeostasis

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