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E3 ubiquitin ligase RNF128 promotes Lys63-linked polyubiquitination on SRB1 in macrophages and aggravates atherosclerosis

Author

Listed:
  • Yapeng Liu

    (Qilu Hospital of Shandong University)

  • Xinyu Zhang

    (Qilu Hospital of Shandong University)

  • Liwen Yu

    (Qilu Hospital of Shandong University)

  • Lei Cao

    (Qilu Hospital of Shandong University)

  • Jie Zhang

    (Qilu Hospital of Shandong University)

  • Qian Li

    (Qilu Hospital of Shandong University)

  • Xiaohong Wang

    (Qilu Hospital of Shandong University)

  • Wenqian Qi

    (Qilu Hospital of Shandong University)

  • Liangyu Cai

    (Qilu Hospital of Shandong University)

  • Ruiqing Ren

    (Qilu Hospital of Shandong University)

  • Weiwei Wang

    (Qilu Hospital of Shandong University)

  • Xiaobin Guo

    (Central Hospital Affiliated to Shandong First Medical University)

  • Guohai Su

    (Central Hospital Affiliated to Shandong First Medical University)

  • Bo Xi

    (Shandong University)

  • Yun Zhang

    (Qilu Hospital of Shandong University
    Central Hospital Affiliated to Shandong First Medical University)

  • Chengjiang Gao

    (Shandong University)

  • Meng Zhang

    (Qilu Hospital of Shandong University
    Central Hospital Affiliated to Shandong First Medical University)

  • Cheng Zhang

    (Qilu Hospital of Shandong University
    Central Hospital Affiliated to Shandong First Medical University)

Abstract

Macrophage-derived foam cell formation is the hallmark of atherosclerotic plaques prominently attributed to excessive lipid uptake and metabolic disorders. As a classic membrane-localized ubiquitin ligase, the role of RNF128 in atherosclerosis remains unknown. We discover that RNF128 is specifically expressed in macrophages of the lipid core based on single-cell RNA sequencing data and persistent hyperlipidemia induces the high expression of RNF128 in macrophages. RNF128 ablation in macrophages ameliorates atherosclerosis in both male and female mice under the background of ApoE and LDLR deficiency. Mechanistically, RNF128 directly binds to scavenger receptor B1 (SRB1), preventing its degradation through the lysosomal system and promoting oxidized low-density lipoprotein (oxLDL)-induced foam cell formation and inflammatory response in macrophages. In addition, RNF128 catalyzes Lys63-linked polyubiquitination on the cytoplasmic C-terminus of the SRB1 at lysine 478, which promotes the endosome SRB1 recycling to the cell membrane with the assistance of Rab11, instead of entering the lysosome for degradation.

Suggested Citation

  • Yapeng Liu & Xinyu Zhang & Liwen Yu & Lei Cao & Jie Zhang & Qian Li & Xiaohong Wang & Wenqian Qi & Liangyu Cai & Ruiqing Ren & Weiwei Wang & Xiaobin Guo & Guohai Su & Bo Xi & Yun Zhang & Chengjiang Ga, 2025. "E3 ubiquitin ligase RNF128 promotes Lys63-linked polyubiquitination on SRB1 in macrophages and aggravates atherosclerosis," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57404-6
    DOI: 10.1038/s41467-025-57404-6
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    1. Dante Neculai & Michael Schwake & Mani Ravichandran & Friederike Zunke & Richard F. Collins & Judith Peters & Mirela Neculai & Jonathan Plumb & Peter Loppnau & Juan Carlos Pizarro & Alma Seitova & Wil, 2013. "Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36," Nature, Nature, vol. 504(7478), pages 172-176, December.
    2. Peter Libby, 2021. "The changing landscape of atherosclerosis," Nature, Nature, vol. 592(7855), pages 524-533, April.
    3. Linzhang Huang & Ken L. Chambliss & Xiaofei Gao & Ivan S. Yuhanna & Erica Behling-Kelly & Sonia Bergaya & Mohamed Ahmed & Peter Michaely & Kate Luby-Phelps & Anza Darehshouri & Lin Xu & Edward A. Fish, 2019. "SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis," Nature, Nature, vol. 569(7757), pages 565-569, May.
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