Apoptotic signalling targets the post-endocytic sorting machinery of the death receptor Fas/CD95

Shruti Sharma, Antonio Carmona, Agnieszka Skowronek, Fangyan Yu, Mark O. Collins, Sindhu Naik, Claire M. Murzeau, Pei-Li Tseng and Kai S. Erdmann ()
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Shruti Sharma: University of Sheffield
Antonio Carmona: University of Sheffield
Agnieszka Skowronek: University of Sheffield
Fangyan Yu: University of Sheffield
Mark O. Collins: University of Sheffield
Sindhu Naik: University of Sheffield
Claire M. Murzeau: University of Sheffield
Pei-Li Tseng: University of Sheffield
Kai S. Erdmann: University of Sheffield

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Fas plays a major role in regulating ligand-induced apoptosis in many cell types. It is well known that several cancers demonstrate reduced cell surface levels of Fas and thus escape a potential control system via ligand-induced apoptosis, although underlying mechanisms are unclear. Here we report that the endosome associated trafficking regulator 1 (ENTR1), controls cell surface levels of Fas and Fas-mediated apoptotic signalling. ENTR1 regulates, via binding to the coiled coil domain protein Dysbindin, the delivery of Fas from endosomes to lysosomes thereby controlling termination of Fas signal transduction. We demonstrate that ENTR1 is cleaved during Fas-induced apoptosis in a caspase-dependent manner revealing an unexpected interplay of apoptotic signalling and regulation of endolysosomal trafficking resulting in a positive feedback signalling-loop. Our data provide insights into the molecular mechanism of Fas post-endocytic trafficking and signalling, opening possible explanations on how cancer cells regulate cell surface levels of death receptors.

Date: 2019
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DOI: 10.1038/s41467-019-11025-y

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