Ask about this productRelated genes to: ZNRF2 antibody
- Gene:
- ZNRF2 NIH gene
- Name:
- zinc and ring finger 2
- Previous symbol:
- -
- Synonyms:
- RNF202
- Chromosome:
- 7p14.3
- Locus Type:
- gene with protein product
- Date approved:
- 2004-07-29
- Date modifiied:
- 2016-10-05
Related products to: ZNRF2 antibody
Related articles to: ZNRF2 antibody
- Myocardial infarction (MI) remains a major cause of heart failure, largely driven by maladaptive ventricular remodeling and excessive cardiac fibrosis. The IL-33/ST2L axis exerts cardioprotective and anti-fibrotic effects, but how the availability of the membrane receptor ST2L is controlled under stress conditions remains incompletely understood. Here, we investigated whether ubiquitin-proteasome-dependent turnover of ST2L, mediated by the E3 ligase Znrf2, constrains IL-33/ST2L signaling and promotes post-MI fibrosis. Using neonatal mouse cardiac fibroblasts, cycloheximide chase and pharmacological inhibition experiments revealed that ST2L is a short-lived protein degraded predominantly through the proteasome rather than the lysosome. IL-33 stimulation enhanced ST2L internalization and induced robust polyubiquitination, thereby accelerating proteasomal degradation. Candidate screening and gain-of-function analyses identified Znrf2 as a functional E3 ligase-associated regulator of ST2L turnover: Znrf2 overexpression selectively reduced ST2L, but not sST2, in a dose-dependent manner, whereas proteasome inhibition stabilized ST2L. Mapping experiments showed that the Znrf2 zinc-finger domain recognizes a 306-315 amino acid motif in ST2L, and deletion of this motif rendered ST2L resistant to Znrf2-induced degradation. In a mouse MI model, Znrf2 expression was upregulated in the infarcted myocardium, accompanied by increased collagen deposition. Systemic administration of the proteasome inhibitor MG-132 or cardiac-specific Znrf2 knockdown preserved ST2L, particularly at the plasma membrane, attenuated myocardial fibrosis, and improved echocardiographic indices of left ventricular function. Importantly, AAV9-mediated silencing of ST2L blunted the anti-fibrotic and functional benefits of MG-132 and Znrf2 knockdown, indicating that these interventions act, at least in part, through ST2L. Collectively, our data identify Znrf2-dependent ST2L ubiquitination and proteasomal degradation as a negative regulatory mechanism that limits IL-33/ST2L cardioprotection after MI. Targeting the Znrf2-ST2L axis to preserve functional ST2L may represent a promising strategy to restrain post-infarction cardiac fibrosis and remodeling. - Source: PubMed
Publication date: 2026/06/22
Bao HailongHuang RunzeChen XinChen BingxiuCao ZhaoxingZhou WeiYan FeiLi WeiChen Zhangrong - Lysosomal dysfunction is a hallmark of cellular senescence, yet the mechanisms governing lysosomal protein trafficking remain incompletely understood. Here, we show that CD-M6PR, a principal receptor for lysosomal enzyme transport, is markedly reduced in senescent fibroblasts and in aged mice and humans, and that its loss correlates with the severity of autolysosomal impairment. Mechanistically, the reduction of CD-M6PR in senescent cells mainly stems from the accelerated proteasome-mediated degradation. Utilizing structural predictions and experimental validation, we identified the E3 ubiquitin ligase ZNRF2 as a critical mediator of CD-M6PR's rapid degradation in senescent cells, facilitated by ZNRF2's elevated expression in these cells. We further link stress-induced mTORC1 activation to increased ZNRF2 expression, which in turn reduces CD-M6PR protein levels, impairs lysosomal enzyme trafficking, and compromises autolysosomal function, thereby exacerbating cellular senescence. Collectively, these data define a previously unrecognized mTORC1-ZNRF2-CD-M6PR axis and reveal a novel mechanism by which aberrant mTORC1 signaling promotes lysosomal dysfunction and senescence, with potential implications for therapeutic targeting of age-related pathologies. - Source: PubMed
Publication date: 2026/05/01
Zhao TingtingXu WeitongWang FangfangChen HonghanGong HuiYang YuHuang NingYang MingZhang JianGong ChuhuiHuang XiaoliLi YingZhang CuiyingXiao Hengyi - Colorectal cancer (CRC) ranks as the third leading cause of cancer-related deaths worldwide, characterized by genomic heterogeneity arising from ethnic and interindividual differences. Producing region-specific data to characterize ethnic-specific somatic mutations is essential for advancing CRC research. Additionally, accurate somatic mutation detection requires paired tissue analyses to account for interindividual diversity. This study aims to highlight the importance of ethnic diversity in shaping CRC's genomic landscape and emphasize the necessity for region-specific data to refine diagnostic and therapeutic approaches. This study emphasizes the need for region-specific data by analyzing an unprecedented 197 paired samples from the Korean CRC cohort through whole-genome sequencing. We identified 78 potential driver genes. Notably, , , , , and were linked to recurrence, presenting potential therapeutic targets. Our analysis revealed 30 mutational hotspots, with significant variants in (25%, G12A, G12D, G12V), (12%, V2300G), and (8%, R175H). We identified a significant co-occurrence between 12 mutation and 545 mutation. Our findings demonstrate potential driver genes and mutational hotspots associated with CRC patient, characterizing the mutational landscape related to clinical characteristics. Significantly advancing our understanding of CRC's heterogeneous nature, this study lays a solid foundation for devising more efficacious management strategies. - Source: PubMed
Publication date: 2026/01/08
Kang JunhoLim Dong MinKim Young-JoonShim HyeranKim Tae-YouPark Kyu JooKang Sung-BumYu Chang SikLee Jong LyulYu YeuniLee HansongKwon Eun JungKim Hyo MinMun SeongikKwak DongheeLee Hae SeulHeo Hye JinKim Eun KyoungBaek Seung EunPark Jong-WookBae Sung UkKwon Taeg KyuLee DongjunKim KihunOh Chang-KyuKo Dai SikCho SunghwanPark Hae RyounKim ShinKim Yun Hak - Zinc And Ring Finger 2 (ZNRF2), an important protein related to E3 ligases activity, known for its support of cell viability of lung adenocarcinoma (LUAD), remains a functional mystery as its mechanism of action remains largely unknown. SLC3A2, a cell surface transmembrane protein, which regulates intracellular calcium levels and transports L-type amino acids, also has unclear mechanisms, particularly involving its expression and localization. In the present study, we addressed the role of ZNRF2-mediated SLC3A2 plasma membrane translocation, which influences ferroptosis in LUAD. We found that ZNRF2 exhibited ubiquitous expression in LUAD, and supported cell viability via ferroptosis inhibition. Mechanistically, ZNRF2 impacted SLC3A2 membrane localization and ferroptosis by fine-tuning K147-mediated ubiquitination. We subsequently synthesized Peptide K147 to block transportation of the SLC3A2 protein to the plasma membrane, which consequently attenuated the inhibitory effect of ZNRF2 on ferroptosis, thereby preventing tumor cell proliferation both in vitro and in vivo. Finally, we revealed that the ZNRF2- mediated SLC3A2 plasma membrane transport enhanced LUAD chemoresistance, whereas, Peptide K147 facilitated LUAD chemosensitization. Our results demonstrated that ZNRF2-mediated SLC3A2 plasma membrane translocation potentially contributes to the malignant progression and therapeutic resistance in LUAD. This knowledge is beneficial to the future design of advanced cancer therapy. - Source: PubMed
Publication date: 2025/09/25
Zhang WeijieLi JianjunZhao JianLu DiZhang MengzhuMa ChenkangYang YangGu LeiZhu JianjieZeng YuanyuanHuang Jian-AnLiu Zeyi - Renal ischemia-reperfusion injury (RIRI) is characterized by a surge of oxidative stress, lipid peroxidation, and mitochondrial dysfunction, leading to ferroptotic tubular cell death and renal impairment. Recent findings implicate ZNRF2, a RING-type E3 ubiquitin ligase localized to the endo‑lysosomal membrane, as a central regulator that integrates ubiquitin-mediated signaling, ferroptosis susceptibility, and mitochondrial quality control (MQC) pathways. In this review, we synthesize current evidence on ZNRF2's structural features, ubiquitination targets (e.g., GPX4, SLC7A11, NCOA4), and its modulation of key MQC processes-DRP1-driven mitochondrial fission, PINK1-Parkin-mediated mitophagy, and lysosomal clearance via mTORC1/TFEB axis. We propose a temporal model aligning ischemia and reperfusion phases with specific redox and cell-death events, and highlight testable hypotheses such as ZNRF2's control over GPX4 stability or ferritinophagy dynamics. Moreover, we discuss therapeutic perspectives, including pharmacological modulators of ZNRF2 activity (small‑molecule stabilizers, PROTACs), and timing-based intervention windows. This integrated mechanistic framework advances understanding of RIRI pathogenesis and opens avenues for novel redox-targeted therapeutic strategies. - Source: PubMed
Publication date: 2025/09/22
Wang KangyuDeng YunXu ChanghongYan RuiWang HaoZhang YalongMan JiangweiYang Li