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The XBP1‒MARCH5‒MFN2 Axis Confers Endoplasmic Reticulum Stress Resistance by Coordinating Mitochondrial Fission and Mitophagy in Melanoma

  • Author Footnotes
    4 These authors contributed equally to this work.
    Huina Wang
    Footnotes
    4 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China

    Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, China
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  • Author Footnotes
    4 These authors contributed equally to this work.
    Xiuli Yi
    Footnotes
    4 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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  • Author Footnotes
    4 These authors contributed equally to this work.
    Sen Guo
    Footnotes
    4 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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  • Sijia Wang
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China

    Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Jinyuan Ma
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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  • Tao Zhao
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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  • Qiong Shi
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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  • Yangzi Tian
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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  • Hao Wang
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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  • Lintao Jia
    Affiliations
    Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, China
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  • Tianwen Gao
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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  • Author Footnotes
    5 These authors contributed equally to this work.
    Chunying Li
    Footnotes
    5 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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  • Author Footnotes
    5 These authors contributed equally to this work.
    Weinan Guo
    Correspondence
    Correspondence: Weinan Guo, Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China.
    Footnotes
    5 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
    Search for articles by this author
  • Author Footnotes
    4 These authors contributed equally to this work.
    5 These authors contributed equally to this work.
      Melanoma cells are relatively resistant to endoplasmic reticulum (ER) stress, which contributes to tumor progression under stressful conditions and renders tolerance to ER stress‒inducing therapeutic agents. Mitochondria are tightly interconnected with ER. However, whether mitochondria play a role in regulating ER stress resistance in melanoma remains elusive. In this study, we reported that the XBP1‒MARCH5‒MFN2 axis conferred ER stress resistance by coordinating mitochondrial fission and mitophagy in melanoma. Our integrative bioinformatics first revealed that the downregulation of mitochondrial genes was highly correlated with unfolded protein response activation in melanoma. Then we proved that mitochondrial fission and mitophagy were prominently induced to contribute to ER stress resistance both in vitro and in vivo by maintaining mitochondrial function. Mechanistically, the activation of IRE1α/ATF6–XBP1 branches of unfolded protein response promoted the transcription of E3 ligase MARCH5 to facilitate the ubiquitination and degradation of MFN2, which thereby triggered mitochondrial fission and mitophagy under ER stress. Together, our findings show a regulatory axis that links mitochondrial fission and mitophagy to the resistance to ER stress. Targeting mitochondrial quality control machinery can be exploited as an approach to reinforce the efficacy of ER stress‒inducing agents against cancer.

      Abbreviations:

      ATP (adenosine triphosphate), CQ (chloroquine), ER (endoplasmic reticulum), mdivi-1 (mitochondrial division inhibitor 1), TG (thapsigargin), TM (tunicamycin), UPR (unfolded protein response)
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