Nucleophosmin 1 promotes mucosal immunity by supporting mitochondrial oxidative phosphorylation and ILC3 activity
Nucleophosmin 1 (NPM1) is commonly mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia. Concurrent inflammatory bowel diseases (IBD) and MDS are common, indicating a close relationship between IBD and MDS. Here we examined the function of NPM1 in IBD and colitis-associated colorectal cancer (CAC). NPM1 expression was reduced in patients with IBD. Npm1<sup>+/-</sup> mice were more susceptible to acute colitis and experimentally induced CAC than littermate controls. Npm1 deficiency impaired the function of interleukin-22 (IL-22)-producing group three innate lymphoid cells (ILC3s). Mice lacking Npm1 in ILC3s exhibited decreased IL-22 production and accelerated development of colitis. NPM1 was important for mitochondrial biogenesis and metabolism by oxidative phosphorylation in ILC3s. Further experiments revealed that NPM1 cooperates with p65 to promote mitochondrial transcription factor A (TFAM) transcription in ILC3s. Overexpression of Npm1 in mice enhanced ILC3 function and reduced the severity of dextran sulfate sodium-induced colitis. Thus, our findings indicate that NPM1 in ILC3s protects against IBD by regulating mitochondrial metabolism through a p65-TFAM axis.
Authors
- Dejing Pan
- Jinlin Pan
- Hong Lei (ORCID: https://orcid.org/0000-0002-4548-4526)
- Dingsan Luo (ORCID: https://orcid.org/0000-0001-7379-1876)
- Jinyun Yuan (ORCID: https://orcid.org/0000-0002-6559-1599)
- Yunjiao Zhai
- Yanxiang Liu (ORCID: https://orcid.org/0000-0002-3715-8325)
- Ruilong Xia (ORCID: https://orcid.org/0000-0002-2728-2058)
- Guohua Shi (ORCID: https://orcid.org/0000-0002-6836-1617)
- Rongchuan Zhao
- Changgeng Peng (ORCID: https://orcid.org/0000-0002-6707-2717)
- Shaheryar Shafi (ORCID: https://orcid.org/0000-0002-1936-4838)
- Yuanshuai Zhou (ORCID: https://orcid.org/0000-0003-0007-4723)
- Minxuan Sun (ORCID: https://orcid.org/0000-0003-2033-6268)
- Jiao Yang (ORCID: https://orcid.org/0000-0002-1553-5425)
- Shiyang Li (ORCID: https://orcid.org/0000-0003-1487-4991)
- Detian Yuan
- Ruobing Zhang (ORCID: https://orcid.org/0000-0002-4682-2961)
- Hong Zhang (ORCID: https://orcid.org/0000-0002-0430-2319)
Institutions
- Tongji University (CN)
- University of Science and Technology of China (CN)
- Shandong University (CN)
- Soochow University (CN)
- Suzhou Institute of Biomedical Engineering and Technology (CN)
- Suzhou Municipal Hospital (CN)
- Advanced Medical Research Institute (US)
- Nanjing University (CN)
Publication Details
- Journal
- Nature Immunology
- Published
- 2024-08-05
- DOI
- https://doi.org/10.1038/s41590-024-01921-x
- Citations
- 17
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 4.09