Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice

作者：Muna Al-Habsi, Kenji Chamoto, Ken Matsumoto, Norimichi Nomura, Baihao Zhang, Yuki Sugiura, Kazuhiro Sonomura, Aprilia Maharani, Yuka Nakajima, Yibo Wu, Yayoi Nomura, Rosemary J. Menzies, Masaki Tajima, Koji Kitaoka, Yasuharu Haku, Sara Delghandi, Keiko Yurimoto, Fumihiko Matsuda, So Iwata, Toshihiko Ogura, Sidonia Fagarasan, Tasuku Honjo · 发表于：Science · 年份：2022 · DOI：10.1126/science.abj3510 · 被引用次数：213 · 研究领域：Polyamine Metabolism and Applications、Antimicrobial Peptides and Activities、Protein Hydrolysis and Bioactive Peptides

Spermidine (SPD) delays age-related pathologies in various organisms. SPD supplementation overcame the impaired immunotherapy against tumors in aged mice by increasing mitochondrial function and activating CD8 + T cells. Treatment of naïve CD8 + T cells with SPD acutely enhanced fatty acid oxidation. SPD conjugated to beads bound to the mitochondrial trifunctional protein (MTP). In the MTP complex, synthesized and purified from Escherichia coli , SPD bound to the α and β subunits of MTP with strong affinity and allosterically enhanced their enzymatic activities. T cell–specific deletion of the MTP α subunit abolished enhancement of programmed cell death protein 1 (PD-1) blockade immunotherapy by SPD, indicating that MTP is required for SPD-dependent T cell activation.