Department of Chemistry, School of Natural Science, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.
X-Dynamic Research Center, UNIST, Ulsan, Republic of Korea.
Nat Commun. 2024 May 13;15(1):4025. doi: 10.1038/s41467-024-47634-5.
Intracellular membranes composing organelles of eukaryotes include membrane proteins playing crucial roles in physiological functions. However, a comprehensive understanding of the cellular responses triggered by intracellular membrane-focused oxidative stress remains elusive. Herein, we report an amphiphilic photocatalyst localised in intracellular membranes to damage membrane proteins oxidatively, resulting in non-canonical pyroptosis. Our developed photocatalysis generates hydroxyl radicals and hydrogen peroxides via water oxidation, which is accelerated under hypoxia. Single-molecule magnetic tweezers reveal that photocatalysis-induced oxidation markedly destabilised membrane protein folding. In cell environment, label-free quantification reveals that oxidative damage occurs primarily in membrane proteins related to protein quality control, thereby aggravating mitochondrial and endoplasmic reticulum stress and inducing lytic cell death. Notably, the photocatalysis activates non-canonical inflammasome caspases, resulting in gasdermin D cleavage to its pore-forming fragment and subsequent pyroptosis. These findings suggest that the oxidation of intracellular membrane proteins triggers non-canonical pyroptosis.
真核生物细胞器的细胞内膜包含在生理功能中起关键作用的膜蛋白。然而，对于细胞内膜聚焦的氧化应激所引发的细胞反应，我们仍缺乏全面的认识。在此，我们报告了一种定位于细胞内膜的两亲性光催化剂，该催化剂通过氧化作用破坏膜蛋白，导致非典型的细胞焦亡。我们开发的光催化作用通过水氧化产生羟基自由基和过氧化氢，在缺氧下会加速这一过程。单分子磁镊揭示了光催化诱导的氧化显著破坏了膜蛋白的折叠。在细胞环境中，无标记定量分析显示，氧化损伤主要发生在与蛋白质质量控制相关的膜蛋白上，从而加剧线粒体和内质网应激，并诱导裂解性细胞死亡。值得注意的是，光催化作用激活了非典型的炎性小体半胱天冬酶，导致gasdermin D 切割为其形成孔的片段，并随后发生细胞焦亡。这些发现表明，细胞内膜蛋白的氧化引发了非典型的细胞焦亡。
