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Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury.

ABSTRACT: Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.

SUBMITTER: Chu LK

PROVIDER: S-EPMC10728081 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury.

Chu Li-Kai LK Cao Xu X Wan Lin L Diao Qiang Q Zhu Yu Y Kan Yu Y Ye Li-Li LL Mao Yi-Ming YM Dong Xing-Qiang XQ Xiong Qian-Wei QW Fu Ming-Cui MC Zhang Ting T Zhou Hui-Ting HT Cai Shi-Zhong SZ Ma Zhou-Rui ZR Hsu Ssu-Wei SW Wu Reen R Chen Ching-Hsien CH Yan Xiang-Ming XM Liu Jun J

Nature communications 20231218 1

Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We furth ...[more]

PMID: 38110369

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Project description:BackgroundGastric cancer is one of the most prevalent malignant tumors within the digestive system, and ferroptosis playing a crucial role in its progression. Glutathione peroxidase 4 (GPX4), a key negative regulator of ferroptosis, is highly expressed in gastric cancer and contributes to tumor growth. Targeting the regulation of GPX4 has emerged as a promising approach to induce ferroptosis and develop effective therapy for gastric cancer.MethodsTo confirm that OTUD5 is a deubiquitinase of GPX4 and regulates ferroptosis, we performed Western blotting, Co-IP, immunofluorescence, quantitative real-time PCR, Ub assay and flow cytometry experiments. To explore the physiological function of OUTD5, we knocked out the Otud5 gene in the mouse gastric cancer cell line (MFC) using CRISPR-Cas9 and eatablished the subcutaneous tumour model. Immunohistochemistry (IHC) analysis was used to inveatigate the pathological correlation in human gastric cancer.ResultsWe report that ovarian tumor domain-containing 5 (OTUD5) interacts with, deubiquitylates and stabilizes GPX4. OTUD5 depletion destabilizes GPX4, promotes lipid peroxidation and sensitizes gastric cancer cells to ferroptosis. Moreover, the p53 activator nutlin-3a suppresses OTUD5 transcription, leading to GPX4 degradation and ferroptosis of gastric cancer cells. Notably, only wild-type p53 has the capacity to inhibit OTUD5 transcription, while p53 mutations or deficiencies correlate with increased OTUD5 expression, promoting gastric cancer progression. Additionally, OTUD5 silencing and nutlin-3a-induced GPX4 degradation enhances the sensitivity of gastric cancer cells to ferroptosis in vivo. Subsequently, the p53/OTUD5/GPX4 axis is confirmed in clinical gastric cancer samples.ConclusionCollectively, these findings elucidate a mechanism whereby p53 inactivation upregulates OTUD5 transcription to deubiquitylate and stablize GPX4, resulting in ferroptosis inhibition and gastric cancer progression. This discovery highlights the potential therapeutic value of targeting OTUD5 to promote ferroptosis in p53-inactivated gastric cancer.Key pointsOTUD5 mediates GPX4 deubiquitination to regulate its stability. Deletion of OTUD5 promotes ferroptosis and inhibits tumor growth. Wild type p53 inhibits OTUD5 transcription, thereby promoting GPX4 degradation and inhibiting the development of gastric cancer. OTUD5, GPX4 expression and p53 activity are highly correlated and correlates with clinical progression in STAD.

Dataset Information

Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury.

Publications

Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury.

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