IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-26987-1.html
   My bibliography  Save this article

The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages

Author

Listed:
  • Kelvin Ka Lok Wu

    (The Hong Kong Polytechnic University)

  • KeKao Long

    (The Hong Kong Polytechnic University)

  • Huige Lin

    (The Hong Kong Polytechnic University)

  • Parco Ming Fai Siu

    (School of Public Health, The University of Hong Kong)

  • Ruby Lai Chong Hoo

    (The State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong
    The University of Hong Kong)

  • Dewei Ye

    (Guangdong Research Center of Metabolic Diseases of Integrated Western and Chinese Medicine, Guangdong Pharmaceutical University)

  • Aimin Xu

    (The State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong
    The University of Hong Kong
    The University of Hong Kong)

  • Kenneth King Yip Cheng

    (The Hong Kong Polytechnic University)

Abstract

Although mitophagy is known to restrict NLRP3 inflammasome activation, the underlying regulatory mechanism remains poorly characterized. Here we describe a type of early endosome-dependent mitophagy that limits NLRP3 inflammasome activation. Deletion of the endosomal adaptor protein APPL1 impairs mitophagy, leading to accumulation of damaged mitochondria producing reactive oxygen species (ROS) and oxidized cytosolic mitochondrial DNA, which in turn trigger NLRP3 inflammasome overactivation in macrophages. NLRP3 agonist causes APPL1 to translocate from early endosomes to mitochondria, where it interacts with Rab5 to facilitate endosomal-mediated mitophagy. Mice deficient for APPL1 specifically in hematopoietic cell are more sensitive to endotoxin-induced sepsis, obesity-induced inflammation and glucose dysregulation. These are associated with increased expression of systemic interleukin-1β, a major product of NLRP3 inflammasome activation. Our findings indicate that the early endosomal machinery is essential to repress NLRP3 inflammasome hyperactivation by promoting mitophagy in macrophages.

Suggested Citation

  • Kelvin Ka Lok Wu & KeKao Long & Huige Lin & Parco Ming Fai Siu & Ruby Lai Chong Hoo & Dewei Ye & Aimin Xu & Kenneth King Yip Cheng, 2021. "The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26987-1
    DOI: 10.1038/s41467-021-26987-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-26987-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-26987-1?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. Babette C. Hammerling & Rita H. Najor & Melissa Q. Cortez & Sarah E. Shires & Leonardo J. Leon & Eileen R. Gonzalez & Daniela Boassa & Sébastien Phan & Andrea Thor & Rebecca E. Jimenez & Hong Li & Ric, 2017. "A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance," Nature Communications, Nature, vol. 8(1), pages 1-16, April.
    2. Zhenyu Zhong & Shuang Liang & Elsa Sanchez-Lopez & Feng He & Shabnam Shalapour & Xue-jia Lin & Jerry Wong & Siyuan Ding & Ekihiro Seki & Bernd Schnabl & Andrea L. Hevener & Harry B. Greenberg & Tatian, 2018. "New mitochondrial DNA synthesis enables NLRP3 inflammasome activation," Nature, Nature, vol. 560(7717), pages 198-203, August.
    3. Jueqi Chen & Zhijian J. Chen, 2018. "PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation," Nature, Nature, vol. 564(7734), pages 71-76, December.
    4. Tatsuya Saitoh & Naonobu Fujita & Myoung Ho Jang & Satoshi Uematsu & Bo-Gie Yang & Takashi Satoh & Hiroko Omori & Takeshi Noda & Naoki Yamamoto & Masaaki Komatsu & Keiji Tanaka & Taro Kawai & Tohru Ts, 2008. "Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production," Nature, Nature, vol. 456(7219), pages 264-268, 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. Shouya Feng & Daniel Enosi Tuipulotu & Abhimanu Pandey & Weidong Jing & Cheng Shen & Chinh Ngo & Melkamu B. Tessema & Fei-Ju Li & Daniel Fox & Anukriti Mathur & Anyang Zhao & Runli Wang & Klaus Pfeffe, 2022. "Pathogen-selective killing by guanylate-binding proteins as a molecular mechanism leading to inflammasome signaling," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Longjun Li & Rudi Mao & Shenli Yuan & Qingqing Xie & Jinyu Meng & Yu Gu & Siyu Tan & Xiaoqing Xu & Chengjiang Gao & Hongbin Liu & Chunhong Ma & Si Ming Man & Xiangbo Meng & Tao Xu & Xiaopeng Qi, 2024. "NCF4 attenuates colorectal cancer progression by modulating inflammasome activation and immune surveillance," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Naijun Miao & Zhuning Wang & Qinlan Wang & Hongyan Xie & Ninghao Yang & Yanzhe Wang & Jin Wang & Haixia Kang & Wenjuan Bai & Yuanyuan Wang & Rui He & Kepeng Yan & Yang Wang & Qiongyi Hu & Zhaoyuan Liu, 2023. "Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    4. Ayesha Sen & Sebastian Kallabis & Felix Gaedke & Christian Jüngst & Julia Boix & Julian Nüchel & Kanjanamas Maliphol & Julia Hofmann & Astrid C. Schauss & Marcus Krüger & Rudolf J. Wiesner & David Pla, 2022. "Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    5. Lucia Taraborrelli & Yasin Şenbabaoğlu & Lifen Wang & Junghyun Lim & Kerrigan Blake & Noelyn Kljavin & Sarah Gierke & Alexis Scherl & James Ziai & Erin McNamara & Mark Owyong & Shilpa Rao & Aslihan Ka, 2023. "Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Zhi Feng & Shengnan Liu & Ming Su & Chunyu Song & Chenyu Lin & Fangying Zhao & Yang Li & Xianyan Zeng & Yong Zhu & Yu Hou & Chunguang Ren & Huan Zhang & Ping Yi & Yong Ji & Chao Wang & Hongtao Li & Mi, 2024. "TANGO6 regulates cell proliferation via COPI vesicle-mediated RPB2 nuclear entry," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. 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.
    8. Man Chen & Madhav C. Menon & Wenlin Wang & Jia Fu & Zhengzi Yi & Zeguo Sun & Jessica Liu & Zhengzhe Li & Lingyun Mou & Khadija Banu & Sui-Wan Lee & Ying Dai & Nanditha Anandakrishnan & Evren U. Azelog, 2023. "HCK induces macrophage activation to promote renal inflammation and fibrosis via suppression of autophagy," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    9. Lauriane Galle-Treger & Doumet Georges Helou & Christine Quach & Emily Howard & Benjamin P. Hurrell & German R. Aleman Muench & Pedram Shafiei-Jahani & Jacob D. Painter & Andrea Iorga & Lily Dara & Ju, 2022. "Autophagy impairment in liver CD11c+ cells promotes non-alcoholic fatty liver disease through production of IL-23," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Wenjing Liang & Shakti Sagar & Rishith Ravindran & Rita H. Najor & Justin M. Quiles & Liguo Chi & Rachel Y. Diao & Benjamin P. Woodall & Leonardo J. Leon & Erika Zumaya & Jason Duran & David M. Cauvi , 2023. "Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired," Nature Communications, Nature, vol. 14(1), pages 1-18, 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:12:y:2021:i:1:d:10.1038_s41467-021-26987-1. 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.