Targeting type I DED interactions at the DED filament serves as a sensitive switch for cell fate decisions,Cell Chemical Biology

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Targeting type I DED interactions at the DED filament serves as a sensitive switch for cell fate decisions
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2024-07-24 , DOI: 10.1016/j.chembiol.2024.06.014
Corinna König ₁ , Nikita V Ivanisenko ₁ , Laura K Hillert-Richter ₁ , Deepti Namjoshi ₂ , Kalyani Natu ₃ , Johannes Espe ₁ , Dirk Reinhold ₄ , Nikolai A Kolchanov ₅ , Vladimir A Ivanisenko ₆ , Thilo Kähne ₇ , Kakoli Bose ₃ , Inna N Lavrik ₁

Affiliation

Translational Inflammation Research, Medical Faculty, Center of Dynamic Systems, Otto von Guericke University, Magdeburg, Germany.
Integrated Biophysics and Structural Biology Lab, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Mumbai, India.
Integrated Biophysics and Structural Biology Lab, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Mumbai, India; Homi Bhabha National Institute, BARC Training School Complex, Mumbai, India.
Institute of Molecular and Clinical immunology, Medical Faculty, Otto von Guericke University, Magdeburg, Germany.
Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia; Kurchatov Genomics Center, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia.
Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia; Kurchatov Genomics Center, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia; State Novosibirsk University, Novosibirsk, Russia.
Institute of Experimental and Internal Medicine (iEIM), Medical Faculty, Otto von Guericke University, Magdeburg, Germany.

Activation of procaspase-8 in the death effector domain (DED) filaments of the death-inducing signaling complex (DISC) is a key step in apoptosis. In this study, a rationally designed cell-penetrating peptide, DEDid, was engineered to mimic the h2b helical region of procaspase-8-DED2 containing a highly conservative FL motif. Furthermore, mutations were introduced into the DEDid binding site of the procaspase-8 type I interface. Additionally, our data suggest that DEDid targets other type I DED interactions such as those of FADD. Both approaches of blocking type I DED interactions inhibited CD95L-induced DISC assembly, caspase activation and apoptosis. We showed that inhibition of procaspase-8 type I interactions by mutations not only diminished procaspase-8 recruitment to the DISC but also destabilized the FADD core of DED filaments. Taken together, this study offers insights to develop strategies to target DED proteins, which may be considered in diseases associated with cell death and inflammation.

中文翻译：

在 DED 细丝上靶向 I 型 DED 相互作用是细胞命运决策的敏感开关

死亡诱导信号转导复合物（DISC）的死亡效应结构域（DED）细丝中 procaspase-8 的激活是细胞凋亡的关键步骤。在这项研究中，设计合理设计的细胞穿透肽 DEDid 来模拟含有高度保守 FL 基序的 procaspase-8-DED2 的 h2b 螺旋区域。此外，突变被引入 procaspase-8 I 型界面的 DEDid 结合位点。此外，我们的数据表明 DEDid 针对其他 I 型 DED 相互作用，例如 FADD 的相互作用。阻断 I 型 DED 相互作用的两种方法都抑制了 CD95L 诱导的 DISC 组装、半胱天冬酶激活和细胞凋亡。我们发现，突变对 procaspase-8 I 型相互作用的抑制不仅减少了 procaspase-8 向 DISC 的募集，而且还破坏了 DED 丝的 FADD 核心。综上所述，本研究为开发靶向 DED 蛋白的策略提供了见解，这可能被考虑用于与细胞死亡和炎症相关的疾病。

更新日期：2024-07-24

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