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

• Published in: Molecular cell 2023-06, Vol.83 (11), p.1887-1902.e8
• Main Authors: Han, Yi, Zhang, Yan-Yu, Pan, Yi-Qian, Zheng, Xiao-Jun, Liao, Kun, Mo, Hai-Yu, Sheng, Hui, Wu, Qi-Nian, Liu, Ze-Xian, Zeng, Zhao-Lei, Yang, Wei, Yuan, Shu-Qiang, Huang, Peng, Ju, Huai-Qiang, Xu, Rui-Hua
• Format: Article
• Language: English
• Subjects: Acetylation; ferroptosis; Humans; Immunotherapy; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; interleukin-1β; NADP Transhydrogenases - genetics; NADP Transhydrogenases - metabolism; Neoplasms - drug therapy; Neoplasms - genetics; NNT; Protein Processing, Post-Translational
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2023.05.011

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. [Display omitted] •IL-1β induces NNT K1042 acetylation in tumor cells•Acetylation at K1042 enhances NNT activity to orchestrate ISCs maintenance•IL-1β triggers PCAF mitochondrial translocation to catalyze NNT K1042 acetylation•IL-1β-NNT acetylation axis protects tumor cells from ferroptosis and immunotherapy Han et al. demonstrate that IL-1β promotes NNT K1042 acetylation in tumor cells by inducing the mitochondrial translocation of PCAF, which enhances the binding affinity of NNT for its substrate NADP+. K1042-acetylated NNT favors the production of NADPH to maintain intracellular iron-sulfur cluster homeostasis, thereby protecting tumor cells from immunotherapy-induced ferroptosis.