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IL-1β-associated NNT acetylation orchestrates iron-sulfur cluster maintenance and cancer immunotherapy resistance.

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Affiliations

  • 1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P. R. China; Research Department of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510060, P. R. China.
      Authors
    • Han Y 1
    (1 author)
  • 2. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P. R. China.
      Authors
    • Zhang YY 2
    • Pan YQ 2
    • Liao K 2
    • Mo HY 2
    • Sheng H 2
    • Liu ZX 2
    • Zeng ZL 2
    • Huang P 2
    (8 authors)
  • 3. Research Department of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510060, P. R. China.
      Authors
    • Zheng XJ 3
    • Yang W 3
    (2 authors)
  • 4. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P. R. China; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China.
      Authors
    • Wu QN 4
    (1 author)
  • 5. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P. R. China; Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P. R. China.
      Authors
    • Yuan SQ 5
    (1 author)
    • Show all (6)

ORCIDs linked to this article

Molecular Cell, 26 May 2023, 83(11):1887-1902.e8
https://doi.org/10.1016/j.molcel.2023.05.011 PMID: 37244254 

Abstract 

Interleukin-1β (IL-1β) is a key protein in inflammation and contributes to tumor progression. However, the role of IL-1β in cancer is ambiguous or even contradictory. Here, we found that upon IL-1β stimulation, nicotinamide nucleotide transhydrogenase (NNT) in cancer cells is acetylated at lysine (K) 1042 (NNT K1042ac) and thereby induces the mitochondrial translocation of p300/CBP-associated factor (PCAF). This acetylation enhances NNT activity by increasing the binding affinity of NNT for NADP+ and therefore boosts NADPH production, which subsequently sustains sufficient iron-sulfur cluster maintenance and protects tumor cells from ferroptosis. Abrogating NNT K1042ac dramatically attenuates IL-1β-promoted tumor immune evasion and synergizes with PD-1 blockade. In addition, NNT K1042ac is associated with IL-1β expression and the prognosis of human gastric cancer. Our findings demonstrate a mechanism of IL-1β-promoted tumor immune evasion, implicating the therapeutic potential of disrupting the link between IL-1β and tumor cells by inhibiting NNT acetylation.

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Read article at publisher's site: https://doi.org/10.1016/j.molcel.2023.05.011

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Funding 

Funders who supported this work.

CAMS Innovation Fund for Medical Sciences (1)

China Postdoctoral Science Foundation (1)

Chinese Academy of Meteorological Sciences

    National Key Research and Development Program of China (1)

    National Natural Science Foundation of China (3)

    Natural Science Foundation of Guangdong Province (1)