Perfluorooctane sulfonate induced ferritinophagy via detyrosinated alpha tubulin-TRIM21-HERC2-regulated NCOA4 degradation in hepatocytes

IF 7.6 2区 环境科学与生态学 Q1 ENVIRONMENTAL SCIENCES Environmental Pollution Pub Date : 2025-03-20 DOI:10.1016/j.envpol.2025.126101
Ruzhen Feng, Lingli Hu, Wei Yang, Peiyao Liang, Yu Li, Kefan Tian, Kejing Wang, Tianming Qiu, Jingyuan Zhang, Xiance Sun, Xiaofeng Yao
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Abstract

The persistent organic pollutant perfluorooctane sulfonate (PFOS) is demonstrated to induce hepatotoxicity through disrupting iron homeostasis and subsequent ferroptosis in hepatocytes. However, it is still elusive in the mechanisms underneath the dysfunctional iron metabolism caused by PFOS. In this study, we observed that PFOS activated the nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in mice liver and human hepatocytes. PFOS reduced the ubiquitination of NCOA4, subsequently causing an increase in the expression of NCOA4. PFOS induced the ubiquitination of HECT and RLD domain-containing E3 ubiquitin protein ligase 2 (HERC2), an upstream negative regulator of NCOA4, leading to the degradation of HERC2. PFOS upregulated the level of detyrosinated α-tubulin (detyr-α-tubulin) in hepatocytes. Under PFOS exposure, detyr-α-tubulin interacted with tripartite motif containing 21 (TRIM21), another E3 ubiquitin ligase responsible for HERC2 degradation. Despite the reduction in the protein level of HERC2, the increases in detyr-α-tubulin and the interaction between detyr-α-tubulin and TRIM21 caused by PFOS facilitated the interaction between TRIM21 and HERC2. Furthermore, inhibiting α-tubulin detyrosination by parthenolide reversed the ferritinophagy and the following ferroptosis caused by PFOS. Collectively, this study points out the existence of ferritinophagy and enriches the understanding of the alteration in iron metabolism under PFOS exposure, providing novel mechanistic insights into the hepatic toxicity of PFOS.

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来源期刊
Environmental Pollution
Environmental Pollution 环境科学-环境科学
CiteScore
16.00
自引率
6.70%
发文量
2082
审稿时长
2.9 months
期刊介绍: Environmental Pollution is an international peer-reviewed journal that publishes high-quality research papers and review articles covering all aspects of environmental pollution and its impacts on ecosystems and human health. Subject areas include, but are not limited to: • Sources and occurrences of pollutants that are clearly defined and measured in environmental compartments, food and food-related items, and human bodies; • Interlinks between contaminant exposure and biological, ecological, and human health effects, including those of climate change; • Contaminants of emerging concerns (including but not limited to antibiotic resistant microorganisms or genes, microplastics/nanoplastics, electronic wastes, light, and noise) and/or their biological, ecological, or human health effects; • Laboratory and field studies on the remediation/mitigation of environmental pollution via new techniques and with clear links to biological, ecological, or human health effects; • Modeling of pollution processes, patterns, or trends that is of clear environmental and/or human health interest; • New techniques that measure and examine environmental occurrences, transport, behavior, and effects of pollutants within the environment or the laboratory, provided that they can be clearly used to address problems within regional or global environmental compartments.
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