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Volume 41 Issue 3
June 2026
    Citation: Ziyue Li, Yang Wang, Jingbo Qie, Shuangqu Li, Zhaobing Gao, Hin Chu, Bingqing Xia. RNF26 bridges ER stress and autophagy in the clearance of MERS envelope protein .VIROLOGICA SINICA, 2026, 41(3) : 612-623.  http://dx.doi.org/10.1016/j.virs.2026.06.005
    shu

    RNF26 bridges ER stress and autophagy in the clearance of MERS envelope protein

    • a. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China;

    • b. CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;

    • c. University of Chinese Academy of Sciences, Beijing 100049, China;

    • d. State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at the University of Hong Kong, Hong Kong Special Administrative Region, China;

    • e. Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;

    • f. Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China;

    • g. Materials Innovation Institute for Life Sciences and Energy (MILES), HKU-SIRI, Shenzhen 518000, China

    • Corresponding author: Hin Chu, hinchu@hku.hk
      Bingqing Xia, xiabingqing@simm.ac.cn
    • Received Date: 05 December 2025
      Accepted Date: 05 June 2026
      Available online: 09 June 2026
    • Coronavirus envelope (E) proteins are small, highly conserved viroporins essential for virion assembly and pathogenicity. Despite extensive characterization of their ion channel activity, how host cells sense and dispose of excessive viral membrane proteins remains poorly understood. Here we show that expression of the MERS-CoV E protein triggers pronounced ER stress and autophagy activation in human cells. The E protein is selectively degraded through an RNF26-dependent autophagy-lysosome pathway, and inhibition of autophagy or loss of RNF26 function leads to E accumulation and sustained unfolded protein response. Mechanistically, RNF26, an ER-anchored E3 ubiquitin ligase, promotes RING-dependent clearance of the viral protein through an ER protein quality control-associated pathway linked to autophagy and ER stress adaptation. Disruption of this process establishes a self-amplifying ER stress-autophagy feedback loop that exacerbates proteotoxicity. These findings define a membrane homeostatic conflict between viral viroporins and the host defense machinery, and identify RNF26 as a potential therapeutic target for mitigating viroporin-induced cytotoxicity through host-directed intervention.
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      1. Bello-Perez M, Hurtado-Tamayo J, Requena-Platek R, Canton J, Sanchez-Cordon PJ, Fernandez-Delgado R, Enjuanes L, Sola I. 2022. Mers-cov orf4b is a virulence factor involved in the inflammatory pathology induced in the lungs of mice. PLoS Pathog, 18: e1010834.

      2. Cai C, Tang YD, Zhai J, Zheng C. 2022. The ring finger protein family in health and disease. Signal Transduct Target Ther, 7: 300.

      3. Castro-Gonzalez S, Chen Y, Benjamin J, Shi Y, Serra-Moreno R. 2021. Residues t(48) and a(49) in hiv-1 nl4-3 nef are responsible for the counteraction of autophagy initiation, which prevents the ubiquitin-dependent degradation of gag through autophagosomes. Retrovirology, 18: 33.

      4. Chu H, Shuai H, Hou Y, Zhang X, Wen L, Huang X, Hu B, Yang D, Wang Y, Yoon C, Wong BH, Li C, Zhao X, Poon VK, Cai JP, Wong KK, Yeung ML, Zhou J, Au-Yeung RK, Yuan S, Jin DY, Kok KH, Perlman S, Chan JF, Yuen KY. 2021. Targeting highly pathogenic coronavirus-induced apoptosis reduces viral pathogenesis and disease severity. Sci Adv, 7: eabf8577.

      5. Chu H, Hou Y, Yang D, Wen L, Shuai H, Yoon C, Shi J, Chai Y, Yuen TT, Hu B, Li C, Zhao X, Wang Y, Huang X, Lee KS, Luo C, Cai JP, Poon VK, Chan CC, Zhang AJ, Yuan S, Sit KY, Foo DC, Au WK, Wong KK, Zhou J, Kok KH, Jin DY, Chan JF, Yuen KY. 2022. Coronaviruses exploit a host cysteine-aspartic protease for replication. Nature, 609: 785-792.

      6. Cremer T, Jongsma MLM, Trulsson F, Vertegaal ACO, Neefjes J, Berlin I. 2021. The er-embedded ube2j1/rnf26 ubiquitylation complex exerts spatiotemporal control over the endolysosomal pathway. Cell Rep, 34: 108659.

      7. Cremer T, Voortman LM, Bos E, Jongsma ML, Ter Haar LR, Akkermans JJ, Talavera Ormeno CM, Wijdeven RH, de Vries J, Kim RQ, Janssen GM, van Veelen PA, Koning RI, Neefjes J, Berlin I. 2023. Rnf26 binds perinuclear vimentin filaments to integrate er and endolysosomal responses to proteotoxic stress. Embo j, 42: e111252.

      8. Echavarria-Consuegra L, Cook GM, Busnadiego I, Lefevre C, Keep S, Brown K, Doyle N, Dowgier G, Franaszek K, Moore NA, Siddell SG, Bickerton E, Hale BG, Firth AE, Brierley I, Irigoyen N. 2021. Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection. PLoS Pathog, 17: e1009644.

      9. Feng Y, Pan Z, Wang Z, Lei Z, Yang S, Zhao H, Wang X, Yu Y, Han Q, Zhang J. 2022. Mers-cov nsp1 regulates autophagic flux via mtor signalling and dysfunctional lysosomes. Emerg Microbes Infect, 11: 2529-2543.

      10. Gassen NC, Niemeyer D, Muth D, Corman VM, Martinelli S, Gassen A, Hafner K, Papies J, Mosbauer K, Zellner A, Zannas AS, Herrmann A, Holsboer F, Brack-Werner R, Boshart M, Muller-Myhsok B, Drosten C, Muller MA, Rein T. 2019. Skp2 attenuates autophagy through beclin1-ubiquitination and its inhibition reduces mers-coronavirus infection. Nat Commun, 10: 5770.

      11. Han SW, Jung BK, Ryu KY. 2021. Regulation of polyubiquitin genes to meet cellular ubiquitin requirement. BMB Rep, 54: 189-195.

      12. Hou P, Wang X, Wang H, Wang T, Yu Z, Xu C, Zhao Y, Wang W, Zhao Y, Chu F, Chang H, Zhu H, Lu J, Zhang F, Liang X, Li X, Wang S, Gao Y, He H. 2023. The orf7a protein of sars-cov-2 initiates autophagy and limits autophagosome-lysosome fusion via degradation of snap29 to promote virus replication. Autophagy, 19: 551-569.

      13. Hsu CY, Huang WR, Chiang IH, Li JY, Munir M, Liu HJ. 2025. Avian reovirus induces autophagy-mediated cargo of progeny viruses to extracellular vesicles and enhancement of virus release. Vet Microbiol, 307: 110627.

      14. Jongsma ML, Berlin I, Wijdeven RH, Janssen L, Janssen GM, Garstka MA, Janssen H, Mensink M, van Veelen PA, Spaapen RM, Neefjes J. 2016. An er-associated pathway defines endosomal architecture for controlled cargo transport. Cell, 166: 152-166.

      15. Klein S, Cortese M, Winter SL, Wachsmuth-Melm M, Neufeldt CJ, Cerikan B, Stanifer ML, Boulant S, Bartenschlager R, Chlanda P. 2020. Sars-cov-2 structure and replication characterized by in situ cryo-electron tomography. Nat Commun, 11: 5885.

      16. Li Q, Liu Q, Li S, Zuo X, Zhou H, Gao Z, Xia B. 2025. Golgi-derived extracellular vesicle production induced by sars-cov-2 envelope protein. Apoptosis, 30: 197-209.

      17. Li S, Bu J, Pan X, Li Q, Zuo X, Xiao G, Du J, Zhang LK, Xia B, Gao Z. 2024. Sars-cov-2 envelope protein-derived extracellular vesicles act as potential media for viral spillover. J Med Virol, 96: e29782.

      18. Liu L, Zhang L, Hao X, Wang Y, Zhang X, Ge L, Wang P, Tian B, Zhang M. 2024. Coronavirus envelope protein activates tmed10-mediated unconventional secretion of inflammatory factors. Nat Commun, 15: 8708.

      19. Minigulov N, Boranbayev K, Bekbossynova A, Gadilgereyeva B, Filchakova O. 2024. Structural proteins of human coronaviruses: What makes them different? Front Cell Infect Microbiol, 14: 1458383.

      20. Mohamud Y, Qu J, Xue YC, Liu H, Deng H, Luo H. 2019. Calcoco2/ndp52 and sqstm1/p62 differentially regulate coxsackievirus b3 propagation. Cell Death Differ, 26: 1062-1076.

      21. Nieto-Torres JL, Verdia-Baguena C, Jimenez-Guardeno JM, Regla-Nava JA, Castano-Rodriguez C, Fernandez-Delgado R, Torres J, Aguilella VM, Enjuanes L. 2015. Severe acute respiratory syndrome coronavirus e protein transports calcium ions and activates the nlrp3 inflammasome. Virology, 485: 330-339.

      22. Otomo C, Metlagel Z, Takaesu G, Otomo T. 2013. Structure of the human atg12∼atg5 conjugate required for lc3 lipidation in autophagy. Nat Struct Mol Biol, 20: 59-66.

      23. Rashid HO, Yadav RK, Kim HR, Chae HJ. 2015. Er stress: Autophagy induction, inhibition and selection. Autophagy, 11: 1956-1977.

      24. Sala C, Ninu A, Balducci V, Allegro G, Montalbano A, Lulli M, Boccitto ML, Guzzolino E, Spinelli V, Arcangeli A, Sartiani L, Cerbai E. 2025. Stable expression of sars-cov-2 envelope viroporin promotes intracellular calcium depletion in human cells: Relevance for endoplasmic reticulum stress, cell proliferation, pluripotency and lineage differentiation. Cell Calcium, 128: 103032.

      25. Schoeman D, Fielding BC. 2019. Coronavirus envelope protein: Current knowledge. Virol J, 16: 69.

      26. Siu KL, Chan CP, Kok KH, Woo PC, Jin DY. 2014. Comparative analysis of the activation of unfolded protein response by spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus hku1. Cell Biosci, 4: 3.

      27. Sucec I, Xia B, Somberg NH, Wang Y, Jo H, Li S, Perrone B, Gao Z, Hong M. 2025. Ion channel structure and function of the mers coronavirus e protein. Sci Adv, 11: eadx1788.

      28. Volovik MV, Denieva ZG, Gifer PK, Rakitina MA, Batishchev OV. 2024. Membrane activity and viroporin assembly for the sars-cov-2 e protein are regulated by cholesterol. Biomolecules, 14: 1061.

      29. Wagh AR, Sulakshane P, Glickman MH. 2023. Alzheimer's disease-associated mutant ubiquitin (ubb(+1)) is secreted through an autophagosome-like vesicle-mediated unconventional pathway. Biochim Biophys Acta Gene Regul Mech, 1866: 194936.

      30. Walczak M, Martens S. 2013. Dissecting the role of the atg12-atg5-atg16 complex during autophagosome formation. Autophagy, 9: 424-425.

      31. Wang L, Ou JH. 2015. Hepatitis c virus and autophagy. Biol Chem, 396: 1215-1222.

      32. Wang P, Tian B, Xiao K, Ji W, Li Z. 2025a. The sars-cov-2 nsp4 t492i mutation promotes double-membrane vesicle formation to facilitate transmission. Virol Sin, 40: 225-235.

      33. Wang Q, Peng Z, Chu P, Gui B, Li Y, Liao L, Zhu Z, Ke F, Wang Y, He L. 2025b. Type ii grass carp reovirus utilizes autophagosomes for viroplasm formation and subclinical persistent infection. J Virol, 99: e0035225.

      34. Williams JM, Chen YJ, Cho WJ, Tai AW, Tsai B. 2023. Reticulons promote formation of er-derived double-membrane vesicles that facilitate sars-cov-2 replication. J Cell Biol, 222: e202203060.

      35. Wolff G, Limpens R, Zevenhoven-Dobbe JC, Laugks U, Zheng S, de Jong AWM, Koning RI, Agard DA, Grunewald K, Koster AJ, Snijder EJ, Barcena M. 2020. A molecular pore spans the double membrane of the coronavirus replication organelle. Science, 369: 1395-1398.

      36. Zhai H, Wang T, Liu D, Pan L, Sun Y, Qiu HJ. 2023. Autophagy as a dual-faced host response to viral infections. Front Cell Infect Microbiol, 13: 1289170.

      37. Zhang Y, Sun H, Pei R, Mao B, Zhao Z, Li H, Lin Y, Lu K. 2021. The sars-cov-2 protein orf3a inhibits fusion of autophagosomes with lysosomes. Cell Discov, 7: 31.

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      RNF26 bridges ER stress and autophagy in the clearance of MERS envelope protein

        Corresponding author: Hin Chu, hinchu@hku.hk
        Corresponding author: Bingqing Xia, xiabingqing@simm.ac.cn
      • a. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China;
      • b. CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
      • c. University of Chinese Academy of Sciences, Beijing 100049, China;
      • d. State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at the University of Hong Kong, Hong Kong Special Administrative Region, China;
      • e. Shanghai Fifth People's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;
      • f. Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China;
      • g. Materials Innovation Institute for Life Sciences and Energy (MILES), HKU-SIRI, Shenzhen 518000, China
      • Received Date: 05 December 2025
      • Accepted Date: 05 June 2026

      Abstract: Coronavirus envelope (E) proteins are small, highly conserved viroporins essential for virion assembly and pathogenicity. Despite extensive characterization of their ion channel activity, how host cells sense and dispose of excessive viral membrane proteins remains poorly understood. Here we show that expression of the MERS-CoV E protein triggers pronounced ER stress and autophagy activation in human cells. The E protein is selectively degraded through an RNF26-dependent autophagy-lysosome pathway, and inhibition of autophagy or loss of RNF26 function leads to E accumulation and sustained unfolded protein response. Mechanistically, RNF26, an ER-anchored E3 ubiquitin ligase, promotes RING-dependent clearance of the viral protein through an ER protein quality control-associated pathway linked to autophagy and ER stress adaptation. Disruption of this process establishes a self-amplifying ER stress-autophagy feedback loop that exacerbates proteotoxicity. These findings define a membrane homeostatic conflict between viral viroporins and the host defense machinery, and identify RNF26 as a potential therapeutic target for mitigating viroporin-induced cytotoxicity through host-directed intervention.

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