Targeting type I DED interactions at the DED filament serves as a sensitive switch for cell fate decisions.

Autor:	König C; Translational Inflammation Research, Medical Faculty, Center of Dynamic Systems, Otto von Guericke University, Magdeburg, Germany., Ivanisenko NV; Translational Inflammation Research, Medical Faculty, Center of Dynamic Systems, Otto von Guericke University, Magdeburg, Germany., Hillert-Richter LK; Translational Inflammation Research, Medical Faculty, Center of Dynamic Systems, Otto von Guericke University, Magdeburg, Germany., Namjoshi D; Integrated Biophysics and Structural Biology Lab, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Mumbai, India., Natu K; 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., Espe J; Translational Inflammation Research, Medical Faculty, Center of Dynamic Systems, Otto von Guericke University, Magdeburg, Germany., Reinhold D; Institute of Molecular and Clinical immunology, Medical Faculty, Otto von Guericke University, Magdeburg, Germany., Kolchanov NA; 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., Ivanisenko VA; 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., Kähne T; Institute of Experimental and Internal Medicine (iEIM), Medical Faculty, Otto von Guericke University, Magdeburg, Germany., Bose K; 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., Lavrik IN; Translational Inflammation Research, Medical Faculty, Center of Dynamic Systems, Otto von Guericke University, Magdeburg, Germany. Electronic address: inna.lavrik@med.ovgu.de.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2024 Nov 21; Vol. 31 (11), pp. 1969-1985.e6. Date of Electronic Publication: 2024 Jul 24.
DOI:	10.1016/j.chembiol.2024.06.014
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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