TXNDC5 protects synovial fibroblasts of rheumatoid arthritis from the detrimental effects of endoplasmic reticulum stress

Lu, Qingming; Wang, Jinguang; Zhang, Xiumei; Tian, Ruixue; Qiao, Li; Ge, Liangpeng; Pan, Jihong; Wang, Lin

doi:10.5582/irdr.2019.01139

Cited by 7 publications

(8 citation statements)

References 30 publications

(35 reference statements)

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“…All these aspects have been described related to SAA [53]. Moreover, TXNDC5 is known to play an important role in inflammation and controlling redox status [10,58,59], its absence made cells are more susceptible to apoptosis in several tissues [21,23], and its expression has been correlated with bad prognosis in multiple types of cancer since it provides more ROS tolerance [10,13,60]. ROS control has been linked to TXNDC5 through JNK/STAT3 and ATF6 pathways, confirming the PDI function to modulate oxidative stress.…”

Section: Discussionmentioning

confidence: 86%

Thioredoxin Domain Containing 5 Suppression Elicits Serum Amyloid A-Containing High-Density Lipoproteins

et al. 2022

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Thioredoxin domain containing 5 (TXNDC5) is a protein disulfide isomerase involved in several diseases related to oxidative stress, energy metabolism and cellular inflammation. In a previous manuscript, a negative association between fatty liver development and hepatic Txndc5 expression was observed. To study the role of TXNDC5 in the liver, we generated Txndc5-deficient mice. The absence of the protein caused an increased metabolic need to gain weight along with a bigger and fatter liver. RNAseq was performed to elucidate the putative mechanisms, showing a substantial liver overexpression of serum amyloid genes (Saa1, Saa2) with no changes in hepatic protein, but discrete plasma augmentation by the gene inactivation. Higher levels of malonyldialdehyde, apolipoprotein A1 and platelet activating factor-aryl esterase activity were also found in serum from Txndc5-deficient mice. However, no difference in the distribution of high-density lipoproteins (HDL)-mayor components and SAA was found between groups, and even the reactive oxygen species decreased in HDL coming from Txndc5-deficient mice. These results confirm the relation of this gene with hepatic steatosis and with a fasting metabolic derive remedying an acute phase response. Likewise, they pose a new role in modulating the nature of HDL particles, and SAA-containing HDL particles are not particularly oxidized.

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Section: Discussionmentioning

confidence: 86%

Thioredoxin Domain Containing 5 Suppression Elicits Serum Amyloid A-Containing High-Density Lipoproteins

et al. 2022

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“…The endoplasmic reticulum is the site of biosynthesis for all secreted and membrane proteins, and the accumulation of unfolded proteins in the endoplasmic reticulum leads to endoplasmic reticulum stress (Lu et al, 2020). The unfolded protein response represents an adaptive mechanism to maintain endoplasmic reticulum homeostasis in response to endoplasmic reticulum stress (Hetz & Saxena, 2017).…”

Section: Discussionmentioning

confidence: 99%

Azithromycin alleviates the severity of rheumatoid arthritis by targeting the unfolded protein response component of glucose‐regulated protein 78 (GRP78)

Zhang

Song

et al. 2021

British J Pharmacology

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Background and Purpose: Azithromycin is a macrolide antibiotic with antiinflammatory properties. We aim to substantiate the treatment potential of azithromycin in rheumatoid arthritis.Experimental Approach: Gene expression profiles were collected by RNA sequencing and the effects of azithromycin were assessed by in vitro and in vivo assays on the effects of azithromycin-mediated blockade of glucose-regulated protein 78 (GRP78).Anti-inflammatory activity of azithromycin was measured in fibroblast-like synoviocytes from rheumatoid arthritis patients and in collagen-induced arthritis in DBA/1 mice. Characterization of the binding of azithromycin to GRP78 was performed using drug affinity responsive target stability, proteomics and cellular thermal shift assays. Azithromycin-mediated inhibition of GRP78 and its relationship to its anti-arthritic activity was assessed.Key Results: Azithromycin reduced proinflammatory factor production, cell migration, invasion and chemoattraction and enhanced apoptosis, reducing the deleterious inflammatory response of rheumatoid arthritis fibroblast-like synoviocytes in vitro.Azithromycin ameliorated the severity of collagen-induced arthritis lesions as efficiently as the TNFα inhibitor etanercept. Transcriptional analyses suggested that azithromycin treatment impairs signalling cascades associated with cholesterol and lipid biosynthesis. GRP78 was identified as a novel target of azithromycin.Azithromycin-mediated activation of the unfolded protein response via the inhibition of GRP78 activity is required not only for inducing the expression of C/EBP-Abbreviations: CHOP, C/EBP homologous protein/DNA damage-inducible transcript 3; DARTS, drug affinity responsive target stability; INSIG, insulin inducible gene; MS, mass spectrometry; qRT-PCR, quantitative real-time PCR; siRNA, small interfering RNA; SREBP, sterol-regulatory element binding protein.Yongli Zhang and Luna Ge contributed equally to this work.

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“…Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that is characterized by joint damage, hyperplasia of synovial tissue, irregular angiogenesis, and bone damage [166][167][168]. TXNDC5 accompanied by multiple genes (table in Section 8) are key players in ER stress associated with synovitis in osteoarthritis, chronic pyrophosphate arthropathy, and rheumatoid arthritis [169][170][171].…”

Section: Txndc5 and Rheumatoid Arthritismentioning

confidence: 99%

Thioredoxin Domain Containing 5 (TXNDC5): Friend or Foe?

Bidooki,

Navarro,

Fernandes

et al. 2024

CIMB

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This review focuses on the thioredoxin domain containing 5 (TXNDC5), also known as endoplasmic reticulum protein 46 (ERp46), a member of the protein disulfide isomerase (PDI) family with a dual role in multiple diseases. TXNDC5 is highly expressed in endothelial cells, fibroblasts, pancreatic β-cells, liver cells, and hypoxic tissues, such as cancer endothelial cells and atherosclerotic plaques. TXNDC5 plays a crucial role in regulating cell proliferation, apoptosis, migration, and antioxidative stress. Its potential significance in cancer warrants further investigation, given the altered and highly adaptable metabolism of tumor cells. It has been reported that both high and low levels of TXNDC5 expression are associated with multiple diseases, such as arthritis, cancer, diabetes, brain diseases, and infections, as well as worse prognoses. TXNDC5 has been attributed to both oncogenic and tumor-suppressive features. It has been concluded that in cancer, TXNDC5 acts as a foe and responds to metabolic and cellular stress signals to promote the survival of tumor cells against apoptosis. Conversely, in normal cells, TXNDC5 acts as a friend to safeguard cells against oxidative and endoplasmic reticulum stress. Therefore, TXNDC5 could serve as a viable biomarker or even a potential pharmacological target.

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TXNDC5 protects synovial fibroblasts of rheumatoid arthritis from the detrimental effects of endoplasmic reticulum stress

Cited by 7 publications

References 30 publications

Thioredoxin Domain Containing 5 Suppression Elicits Serum Amyloid A-Containing High-Density Lipoproteins

Thioredoxin Domain Containing 5 Suppression Elicits Serum Amyloid A-Containing High-Density Lipoproteins

Azithromycin alleviates the severity of rheumatoid arthritis by targeting the unfolded protein response component of glucose‐regulated protein 78 (GRP78)

Thioredoxin Domain Containing 5 (TXNDC5): Friend or Foe?

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