TY - JOUR

T1 - Targeting type I DED interactions at the DED filament serves as a sensitive switch for cell fate decisions

AU - König, Corinna

AU - Ivanisenko, Nikita V.

AU - Hillert-Richter, Laura K.

AU - Namjoshi, Deepti

AU - Natu, Kalyani

AU - Espe, Johannes

AU - Reinhold, Dirk

AU - Kolchanov, Nikolai A.

AU - Ivanisenko, Vladimir A.

AU - Kähne, Thilo

AU - Bose, Kakoli

AU - Lavrik, Inna N.

N1 - We acknowledge the Center for Dynamic Systems (CDS), funded by the EU program ERDF (European Regional Development Fund), the Wilhelm Sander-Stiftung (2017.008.02), Budget project FWNR-2022-0020 and DFG (LA/2386). We thank Karina Guttek for excellent technical assistance. Corinna König was supported by the fellowship of Otto von Guericke University. The authors thank Prof. Irmela Jeremias for providing Jurkat-A3-FADD-KO cells and Leon Perniciaro for proofreading. The authors thank the ITC-Facility, Indian Institute of Technology, Bombay and Biophysics Facility, ACTREC, India for providing the necessary infrastructure for the experiments.

PY - 2024/11/21

Y1 - 2024/11/21

N2 - 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.

AB - 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.

KW - CD95

KW - CD95L

KW - DED filament

KW - DISC

KW - FADD

KW - FL motif

KW - apoptosis

KW - caspase-8

KW - peptide

KW - Humans

KW - Apoptosis/drug effects

KW - Caspase 8/metabolism

KW - Fas-Associated Death Domain Protein/metabolism

KW - Cell-Penetrating Peptides/chemistry

KW - Death Domain Receptor Signaling Adaptor Proteins/metabolism

KW - Fas Ligand Protein/metabolism

UR - https://www.mendeley.com/catalogue/807b7c10-e8ac-3578-8c0b-8e6b0a20a9af/

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85200951564&origin=inward&txGid=228b0c1dfc45e4d5d9363a42a25058e0

U2 - 10.1016/j.chembiol.2024.06.014

DO - 10.1016/j.chembiol.2024.06.014

M3 - Article

C2 - 39053461

VL - 31

SP - 1969-1985.e6

JO - Cell Chemical Biology

JF - Cell Chemical Biology

SN - 2451-9456

IS - 11

ER -