IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-30707-8.html
   My bibliography  Save this article

The Ube2m-Rbx1 neddylation-Cullin-RING-Ligase proteins are essential for the maintenance of Regulatory T cell fitness

Author

Listed:
  • Di Wu

    (Zhejiang University School of Medicine
    Zhejiang University
    Binjiang Institute of Zhejiang University)

  • Haomin Li

    (Zhejiang University School of Medicine)

  • Mingwei Liu

    (National Center for Protein Sciences (Beijing) and Institute of Lifeomics)

  • Jun Qin

    (National Center for Protein Sciences (Beijing) and Institute of Lifeomics)

  • Yi Sun

    (Zhejiang University School of Medicine
    Zhejiang University
    Binjiang Institute of Zhejiang University)

Abstract

Neddylation-mediated activation of Cullin-RING E3 Ligases (CRLs) are necessary for the degradation of specific immune regulatory proteins. However, little is known about how these processes govern the function of regulatory T (Treg) cells. Here we show that mice with Treg cell-specific deletion of Rbx1, a dual E3 for both neddylation and ubiquitylation by CRLs, develop an early-onset fatal inflammatory disorder, characterized by disrupted Treg cell homeostasis and suppressive functions. Specifically, Rbx1 is essential for the maintenance of an effector Treg cell subpopulation, and regulates several inflammatory pathways. Similar but less severe phenotypes are observed in mice having Ube2m, a neddylation E2 conjugation enzyme, deleted in their Treg cells. Interestingly, Treg-specific deletion of Rbx2/Sag or Ube2f, components of a similar but distinct neddylation-CRL complex, yields no obvious phenotype. Thus, our work demonstrates that the Ube2m-Rbx1 axis is specifically required for intrinsic regulatory processes in Treg cells; and that Rbx1 might also play Ube2m-independent roles in maintaining the fitness of Treg cells, suggesting a layer of complexity in neddylation-dependent activation of CRLs.

Suggested Citation

  • Di Wu & Haomin Li & Mingwei Liu & Jun Qin & Yi Sun, 2022. "The Ube2m-Rbx1 neddylation-Cullin-RING-Ligase proteins are essential for the maintenance of Regulatory T cell fitness," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30707-8
    DOI: 10.1038/s41467-022-30707-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-30707-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-30707-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Marc A. Gavin & Jeffrey P. Rasmussen & Jason D. Fontenot & Valeria Vasta & Vincent C. Manganiello & Joseph A. Beavo & Alexander Y. Rudensky, 2007. "Foxp3-dependent programme of regulatory T-cell differentiation," Nature, Nature, vol. 445(7129), pages 771-775, February.
    2. Samuel E. Weinberg & Benjamin D. Singer & Elizabeth M. Steinert & Carlos A. Martinez & Manan M. Mehta & Inmaculada Martínez-Reyes & Peng Gao & Kathryn A. Helmin & Hiam Abdala-Valencia & Laura A. Sena , 2019. "Mitochondrial complex III is essential for suppressive function of regulatory T cells," Nature, Nature, vol. 565(7740), pages 495-499, January.
    3. Di Wu & Yuechen Luo & Wei Guo & Qing Niu & Ting Xue & Fei Yang & Xiaolei Sun & Song Chen & Yuanyuan Liu & Jingru Liu & Zhina Sun & Chunxiao Zhao & Huifang Huang & Fang Liao & Zhongchao Han & Dongming , 2017. "Lkb1 maintains Treg cell lineage identity," Nature Communications, Nature, vol. 8(1), pages 1-14, August.
    4. Dongwen Lv & Pratik Pal & Xingui Liu & Yannan Jia & Dinesh Thummuri & Peiyi Zhang & Wanyi Hu & Jing Pei & Qi Zhang & Shuo Zhou & Sajid Khan & Xuan Zhang & Nan Hua & Qingping Yang & Sebastian Arango & , 2021. "Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    5. Greg M. Delgoffe & Seng-Ryong Woo & Meghan E. Turnis & David M. Gravano & Cliff Guy & Abigail E. Overacre & Matthew L. Bettini & Peter Vogel & David Finkelstein & Jody Bonnevier & Creg J. Workman & Da, 2013. "Stability and function of regulatory T cells is maintained by a neuropilin-1–semaphorin-4a axis," Nature, Nature, vol. 501(7466), pages 252-256, September.
    6. Kai Yang & Daniel Bastardo Blanco & Geoffrey Neale & Peter Vogel & Julian Avila & Clary B. Clish & Chuan Wu & Sharad Shrestha & Sherri Rankin & Lingyun Long & Anil KC & Hongbo Chi, 2017. "Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling," Nature, Nature, vol. 548(7669), pages 602-606, August.
    7. Jinfang Zhang & Xia Bu & Haizhen Wang & Yasheng Zhu & Yan Geng & Naoe Taira Nihira & Yuyong Tan & Yanpeng Ci & Fei Wu & Xiangpeng Dai & Jianping Guo & Yu-Han Huang & Caoqi Fan & Shancheng Ren & Yingha, 2018. "Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance," Nature, Nature, vol. 553(7686), pages 91-95, January.
    8. Teresa A. Soucy & Peter G. Smith & Michael A. Milhollen & Allison J. Berger & James M. Gavin & Sharmila Adhikari & James E. Brownell & Kristine E. Burke & David P. Cardin & Stephen Critchley & Courtne, 2009. "An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer," Nature, Nature, vol. 458(7239), pages 732-736, April.
    9. Hu Zeng & Kai Yang & Caryn Cloer & Geoffrey Neale & Peter Vogel & Hongbo Chi, 2013. "mTORC1 couples immune signals and metabolic programming to establish Treg-cell function," Nature, Nature, vol. 499(7459), pages 485-490, July.
    10. Serena Zacchigna & Valentina Martinelli & Silvia Moimas & Andrea Colliva & Marco Anzini & Andrea Nordio & Alessia Costa & Michael Rehman & Simone Vodret & Cristina Pierro & Giulia Colussi & Lorena Zen, 2018. "Paracrine effect of regulatory T cells promotes cardiomyocyte proliferation during pregnancy and after myocardial infarction," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    11. Weiming Ouyang & Will Liao & Chong T. Luo & Na Yin & Morgan Huse & Myoungjoo V. Kim & Min Peng & Pamela Chan & Qian Ma & Yifan Mo & Dies Meijer & Keji Zhao & Alexander Y. Rudensky & Gurinder Atwal & M, 2012. "Novel Foxo1-dependent transcriptional programs control Treg cell function," Nature, Nature, vol. 491(7425), pages 554-559, November.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Seymour Picciotto & Nicholas DeVita & Chiaowen Joyce Hsiao & Christopher Honan & Sze-Wah Tse & Mychael Nguyen & Joseph D. Ferrari & Wei Zheng & Brian T. Wipke & Eric Huang, 2022. "Selective activation and expansion of regulatory T cells using lipid encapsulated mRNA encoding a long-acting IL-2 mutein," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Jing Liu & Xia Bu & Chen Chu & Xiaoming Dai & John M. Asara & Piotr Sicinski & Gordon J. Freeman & Wenyi Wei, 2023. "PRMT1 mediated methylation of cGAS suppresses anti-tumor immunity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Christophe M. Capelle & Séverine Ciré & Fanny Hedin & Maxime Hansen & Lukas Pavelka & Kamil Grzyb & Dimitrios Kyriakis & Oliver Hunewald & Maria Konstantinou & Dominique Revets & Vera Tslaf & Tainá M., 2023. "Early-to-mid stage idiopathic Parkinson’s disease shows enhanced cytotoxicity and differentiation in CD8 T-cells in females," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    4. Yongchang Zhu & Xiping Zhang & Meng Gao & Yanchao Huang & Yuanqing Tan & Avital Parnas & Sizhong Wu & Delin Zhan & Sheera Adar & Jinchuan Hu, 2024. "Coordination of transcription-coupled repair and repair-independent release of lesion-stalled RNA polymerase II," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Baptiste Lamarthée & Armance Marchal & Soëli Charbonnier & Tifanie Blein & Juliette Leon & Emmanuel Martin & Lucas Rabaux & Katrin Vogt & Matthias Titeux & Marianne Delville & Hélène Vinçon & Emmanuel, 2021. "Transient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    6. María Arroyo & Florian D. Hastert & Andreas Zhadan & Florian Schelter & Susanne Zimbelmann & Cathia Rausch & Anne K. Ludwig & Thomas Carell & M. Cristina Cardoso, 2022. "Isoform-specific and ubiquitination dependent recruitment of Tet1 to replicating heterochromatin modulates methylcytosine oxidation," Nature Communications, Nature, vol. 13(1), pages 1-28, December.
    7. Wenfeng Ren & Zilong Xu & Yating Chang & Fei Ju & Hongning Wu & Zhiqi Liang & Min Zhao & Naizhen Wang & Yanhua Lin & Chenhang Xu & Shengming Chen & Yipeng Rao & Chaolong Lin & Jianxin Yang & Pingguo L, 2024. "Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    8. Moataz Reda & Worapol Ngamcherdtrakul & Molly A. Nelson & Natnaree Siriwon & Ruijie Wang & Husam Y. Zaidan & Daniel S. Bejan & Sherif Reda & Ngoc Ha Hoang & Noah A. Crumrine & Justin P. C. Rehwaldt & , 2022. "Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    9. Niranjana Natarajan & Jonathan Florentin & Ebin Johny & Hanxi Xiao & Scott Patrick O’Neil & Liqun Lei & Jixing Shen & Lee Ohayon & Aaron R. Johnson & Krithika Rao & Xiaoyun Li & Yanwu Zhao & Yingze Zh, 2024. "Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    10. Digant Nayak & Dongwen Lv & Yaxia Yuan & Peiyi Zhang & Wanyi Hu & Anindita Nayak & Eliza A. Ruben & Zongyang Lv & Patrick Sung & Robert Hromas & Guangrong Zheng & Daohong Zhou & Shaun K. Olsen, 2024. "Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Lizhen Zhu & Geng Li & Zhixin Liang & Tuan Qi & Kui Deng & Jiancheng Yu & Yue Peng & Jusheng Zheng & Yan Song & Xing Chang, 2023. "Microbiota-assisted iron uptake promotes immune tolerance in the intestine," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    12. David Bradley & Alan J. Smith & Alecia Blaszczak & Dharti Shantaram & Stephen M. Bergin & Anahita Jalilvand & Valerie Wright & Kathleen L. Wyne & Revati S. Dewal & Lisa A. Baer & Katherine R. Wright &, 2022. "Interferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    13. Ryan P. Wurz & Huan Rui & Ken Dellamaggiore & Sudipa Ghimire-Rijal & Kaylee Choi & Kate Smither & Albert Amegadzie & Ning Chen & Xiaofen Li & Abhisek Banerjee & Qing Chen & Dane Mohl & Amit Vaish, 2023. "Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    14. Srikanth Sadhu & Rajdeep Dalal & Jyotsna Dandotiya & Akshay Binayke & Virendra Singh & Manas Ranjan Tripathy & Vinayaka Das & Sandeep Goswami & Shakti Kumar & Zaigham Abbas Rizvi & Amit Awasthi, 2023. "IL-9 aggravates SARS-CoV-2 infection and exacerbates associated airway inflammation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    15. Zhi Liu & Dong-Sung Lee & Yuqiong Liang & Ye Zheng & Jesse R. Dixon, 2023. "Foxp3 orchestrates reorganization of chromatin architecture to establish regulatory T cell identity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    16. Binod Kumar & Natania S. Field & Dale D. Kim & Asif A. Dar & Yanqun Chen & Aishwarya Suresh & Christopher F. Pastore & Li-Yin Hung & Nadia Porter & Keisuke Sawada & Palak Shah & Omar Elbulok & Emily K, 2022. "The ubiquitin ligase Cul5 regulates CD4+ T cell fate choice and allergic inflammation," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    17. Mike B. Barnkob & Yale S. Michaels & Violaine André & Philip S. Macklin & Uzi Gileadi & Salvatore Valvo & Margarida Rei & Corinna Kulicke & Ji-Li Chen & Vitul Jain & Victoria K. Woodcock & Huw Colin-Y, 2024. "Semaphorin 3A causes immune suppression by inducing cytoskeletal paralysis in tumour-specific CD8+ T cells," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    18. Yue Wang & Dhamotharan Pattarayan & Haozhe Huang & Yueshan Zhao & Sihan Li & Yifei Wang & Min Zhang & Song Li & Da Yang, 2024. "Systematic investigation of chemo-immunotherapy synergism to shift anti-PD-1 resistance in cancer," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    19. Wenjun Xiong & Xueliang Gao & Tiantian Zhang & Baishan Jiang & Ming-Ming Hu & Xia Bu & Yang Gao & Lin-Zhou Zhang & Bo-Lin Xiao & Chuan He & Yishuang Sun & Haiou Li & Jie Shi & Xiangling Xiao & Bolin X, 2022. "USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    20. Kerstin Johann & Toszka Bohn & Fatemeh Shahneh & Natascha Luther & Alexander Birke & Henriette Jaurich & Mark Helm & Matthias Klein & Verena K. Raker & Tobias Bopp & Matthias Barz & Christian Becker, 2021. "Therapeutic melanoma inhibition by local micelle-mediated cyclic nucleotide repression," Nature Communications, Nature, vol. 12(1), pages 1-9, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30707-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.