Gama Alejandro Rodriguez, Miller Tayla, Venkatesan Shriram, Lange Jeffrey J, Wu Jianzheng, Song Xiaoqing, Bradford Dan, Unruh Jay R, Halfmann Randal
Stowers Institute for Medical Research, Kansas City, MO.
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA.
bioRxiv. 2024 Mar 3:2023.03.20.533581. doi: 10.1101/2023.03.20.533581.
Innate immunity protects us in youth but turns against us as we age. The reason for this tradeoff is unclear. Seeking a thermodynamic basis, we focused on death fold domains (DFDs), whose ordered polymerization has been stoichiometrically linked to innate immune signal amplification. We hypothesized that soluble ensembles of DFDs function as phase change batteries that store energy via supersaturation and subsequently release it through nucleated polymerization. Using imaging and FRET-based cytometry to characterize the phase behaviors of all 109 human DFDs, we found that the hubs of innate immune signaling networks encode large nucleation barriers that are intrinsically insulated from cross-pathway activation. We showed via optogenetics that supersaturation drives signal amplification and that the inflammasome is constitutively supersaturated . Our findings reveal that the soluble "inactive" states of adaptor DFDs function as essential, yet impermanent, kinetic barriers to inflammatory cell death, suggesting a thermodynamic driving force for aging.
先天免疫在我们年轻时保护我们，但随着年龄增长却对我们不利。这种权衡的原因尚不清楚。为了寻找热力学基础，我们聚焦于死亡折叠结构域（DFD），其有序聚合在化学计量上与先天免疫信号放大相关联。我们假设DFD的可溶性聚集体充当相变电池，通过过饱和储存能量，随后通过成核聚合释放能量。利用成像和基于荧光共振能量转移（FRET）的细胞术来表征所有109种人类DFD的相行为，我们发现先天免疫信号网络的枢纽编码了大的成核屏障，这些屏障本质上与交叉途径激活绝缘。我们通过光遗传学表明过饱和驱动信号放大，并且炎性小体持续处于过饱和状态。我们的研究结果揭示，衔接子DFD的可溶性“无活性”状态充当炎症细胞死亡的关键但非永久性的动力学屏障，这表明衰老存在热力学驱动力。
