ZC3H4 promotes pulmonary fibrosis via an ER stress-related positive feedback loop

Ghafoor, Hammad; Han, Chunchun; Huang, Jie; Chen, Meng‐Ling; Wang, Sha; Wang, Jing; Chao, Jie

doi:10.1016/j.taap.2021.115856

Cited by 6 publications

(3 citation statements)

References 58 publications

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“…C, control group; H, high-dose group; L, low-dose group; M, medium-dose group proliferation, 23 while ERS may block and inhibit the expression of ZC3H4 through miR-212. 13,24 Here, in mouse testes in vivo and in vitro, we found that circZc3h4-miR212 axis regulating Zc3h4 decreased gradually with growing PCM dose, resulting in reduced cell proliferation and heavier testicular damage.…”

Section: Discussionmentioning

confidence: 78%

The joint action of unfolded protein response, circZc3h4, and circRNA Scar in procymidone‐induced testicular injury in adolescent mice

Xin

et al. 2022

Environmental Toxicology

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Procymidone (PCM) is a low toxicity fungicide, and an endocrine‐disrupting chemical (EDC) that particularly damages the reproductive system of male vertebrates. In present study, adolescent mice in control, low‐, medium‐, and high‐dose groups were orally administered 0 (equal volume of soybean oil), 50, 100, and 200 mg/kg/day PCM, respectively, for 21 days. Additionally, a three‐dimensional culture of mouse testes was performed in vitro, and the control, low dose (0.33 × 10−5 M), medium dose (1 × 10−5 M), and high dose (3 × 10−5 M) PCM groups were established. We have found that, under both in vivo and in vitro conditions, all doses of PCM caused damage to mouse testes. Moreover, the levels of circZc3h4 RNA and Zc3h4 decreased while miR‐212 increased in all treatment groups, with a corresponding rise in circRNA Scar and fall in Atp5b, compared to those in the control group, and all the changes showed a dose–response relationship. Besides, we have identified that low doses of PCM could activate the Ire1‐Xbp1 pathway, whereas the medium and high doses activated the Perk‐Elf2α‐Atf4, Ire1‐Xbp1, and Atf6 pathways. And it is, therefore, speculated that the unfolded protein response (UPR), circZc3h4 and circRNA Scar may have taken joint action in testicular injury in adolescent mice induced by PCM at the no observed adverse effect level (NOAEL, 100 mg/kg/day) and below NOAEL doses.

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Section: Discussionmentioning

confidence: 78%

The joint action of unfolded protein response, circZc3h4, and circRNA Scar in procymidone‐induced testicular injury in adolescent mice

Xin

et al. 2022

Environmental Toxicology

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“…5 C, D), which activates ERS. Based on the tunicamycin dose–response relationship experiment conducted by a previous research group [ 17 ], we set the concentration to 50 μM. Finally, when cells were pretreated with the ERS inhibitor salubrinal, the SiO 2 -CM-induced increases in ZC3H4 and NTRK2 levels were attenuated, suggesting that ERS participates in ZC3H4-mediated anoikis resistance in fibroblasts (Fig.…”

Section: Resultsmentioning

confidence: 99%

A missing piece of the puzzle in pulmonary fibrosis: anoikis resistance promotes fibroblast activation

et al. 2022

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Background Pulmonary fibrosis initiates a pneumonic cascade that leads to fibroblast dysfunction characterized by excess proliferation. Anoikis is a physiological process that ensures tissue development and homeostasis. Researchers have not clearly determined whether disruption of anoikis is involved in pulmonary fibrosis. Results Here, we investigated the mechanism by which silica induces fibroblast activation via anoikis resistance and subsequent fibrosis. Anoikis of lung fibroblasts, alveolar epithelial cells and endothelial cells during the process of fibrosis was detected using CCK-8, western blot, cell count and flow cytometry (FCM) assays. Although the three cell types showed similar increases in proliferation, the expression of NTRK2, a marker of anoikis resistance, was upregulated specifically in fibroblasts, indicating the unique proliferation mechanism of fibroblasts in pulmonary fibrosis, which may be related to anoikis resistance. Furthermore, the CRISPR/Cas9 system was used to investigate the molecular mechanism of anoikis resistance; the SiO2-induced inflammatory response activated the MAPK/PI3K signaling pathway in lung fibroblasts and then induced the expression of the ZC3H4 protein, which specifically mediated anoikis resistance, followed by pulmonary fibrosis. Conclusions The current study revealed a specific pattern of fibroblast proliferation, and strategies targeting anoikis resistance may inhibit the pathological process of pulmonary fibrosis. This result provides a new approach for treating pulmonary fibrosis and new insights into the potential application of ZC3H4 in the development of novel therapeutic strategies for mitigating pulmonary fibrosis.

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“…A recent study demonstrated that ATF6 transcriptionally controls the expression of thioredoxin domain-containing protein 5 (TXNDC5), which promotes fibrosis by enhancing TGF-β signaling activity in kidney fibroblasts ( 89 ). ER stress can activate fibroblasts and promote pulmonary fibrosis through a positive feedback loop with ZC3H4, a recently discovered member of the CCCH-type zinc finger protein family ( 90 ). These data suggest that ER stress plays a crucial role in fibroblast activation and could be a potential target for regulating fibrosis in cGVHD ( Figure 1 ).…”

Section: The Contribution Of Upr In Gvhd Developmentmentioning

confidence: 99%

ER stress: an emerging regulator in GVHD development

Choi,

2023

Front. Immunol.

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Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising therapeutic option for hematologic malignancies. However, the clinical benefits of allo-HCT are limited by the development of complications including graft-versus-host disease (GVHD). Conditioning regimens, such as chemotherapy and irradiation, which are administered to the patients prior to allo-HCT, can disrupt the endoplasmic reticulum (ER) homeostasis, and induce ER stress in the recipient’s cells. The conditioning regimen activates antigen-presenting cells (APCs), which, in turn, activate donor cells, leading to ER stress in the transplanted cells. The unfolded protein response (UPR) is an evolutionarily conserved signaling pathway that manages ER stress in response to cellular stress. UPR has been identified as a significant regulatory player that influences the function of various immune cells, including T cells, B cells, macrophages, and dendritic cells (DCs), in various disease progressions. Therefore, targeting the UPR pathway has garnered significant attention as a promising approach for the treatment of numerous diseases, such as cancer, neurodegeneration, diabetes, and inflammatory diseases. In this review, we summarize the current literature regarding the contribution of ER stress response to the development of GVHD in both hematopoietic and non-hematopoietic cells. Additionally, we explore the potential therapeutic implications of targeting UPR to enhance the effectiveness of allo-HCT for patients with hematopoietic malignancies.

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ZC3H4 promotes pulmonary fibrosis via an ER stress-related positive feedback loop

Cited by 6 publications

References 58 publications

The joint action of unfolded protein response, circZc3h4, and circRNA Scar in procymidone‐induced testicular injury in adolescent mice

The joint action of unfolded protein response, circZc3h4, and circRNA Scar in procymidone‐induced testicular injury in adolescent mice

A missing piece of the puzzle in pulmonary fibrosis: anoikis resistance promotes fibroblast activation

ER stress: an emerging regulator in GVHD development

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