2. Academic Validation
  3. NCF4 attenuates colorectal cancer progression by modulating inflammasome activation and immune surveillance

NCF4 attenuates colorectal cancer progression by modulating inflammasome activation and immune surveillance

  • Nat Commun. 2024 Jun 17;15(1):5170. doi: 10.1038/s41467-024-49549-7.
Longjun Li # 1,  Rudi Mao # 1,  Shenli Yuan # 2,  Qingqing Xie 1,  Jinyu Meng 1,  Yu Gu 3,  Siyu Tan 4,  Xiaoqing Xu 5,  Chengjiang Gao 4,  Hongbin Liu 6,  Chunhong Ma 4,  Si Ming Man 7,  Xiangbo Meng 8,  Tao Xu 9,  Xiaopeng Qi 10 11
Affiliations

Affiliations

  • 1 Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
  • 2 CAS Key Laboratory of Genome Sciences and Information, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, and China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, 100101, China.
  • 3 State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
  • 4 Department of Immunology, Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Provincial Key Laboratory of Infection & Immunology, School of Basic Medical Science, Shandong University, Jinan, Shandong, China.
  • 5 Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.
  • 6 Center for Reproductive Medicine, Cheeloo College of Medicine, Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China.
  • 7 Division of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia. siming.man@anu.edu.au.
  • 8 Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China. xbmeng@sdu.edu.cn.
  • 9 Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China. tao.xu@sdu.edu.cn.
  • 10 Key Laboratory for Experimental Teratology of the Ministry of Education, Advanced Medical Research Institute, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China. xqi@email.sdu.edu.cn.
  • 11 National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Jinan, Shandong, China. xqi@email.sdu.edu.cn.
  • # Contributed equally.
PMID: 38886341 DOI: 10.1038/s41467-024-49549-7
Abstract

The spatiotemporal regulation of inflammasome activation remains unclear. To examine the mechanism underlying the assembly and regulation of the inflammasome response, here we perform an immunoprecipitation-mass spectrometry analysis of apoptosis-associated speck-like protein containing a CARD (ASC) and identify NCF4/1/2 as ASC-binding proteins. Reduced NCF4 expression is associated with colorectal Cancer development and decreased five-year survival rate in patients with colorectal Cancer. NCF4 cooperates with NCF1 and NCF2 to promote NLRP3 and AIM2 inflammasome activation. Mechanistically, NCF4 phosphorylation and puncta distribution switches from the NADPH complex to the perinuclear region, mediating ASC oligomerization, speck formation and inflammasome activation. NCF4 functions as a sensor of ROS levels, to establish a balance between ROS production and inflammasome activation. NCF4 deficiency causes severe colorectal Cancer in mice, increases transit-amplifying and precancerous cells, reduces the frequency and activation of CD8+ T and NK cells, and impairs the inflammasome-IL-18-IFN-γ axis during the early phase of colorectal tumorigenesis. Our study implicates NCF4 in determining the spatial positioning of inflammasome assembly and contributing to inflammasome-mediated anti-tumor responses.

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