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; Kai S Erdmann

doi:10.1038/s41467-019-11025-y

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

Nat Commun. 2019 Jul 15;10(1):3105. doi: 10.1038/s41467-019-11025-y.

Authors

Shruti Sharma¹, Antonio Carmona¹, Agnieszka Skowronek¹, Fangyan Yu^{1

2}, Mark O Collins¹, Sindhu Naik¹, Claire M Murzeau¹, Pei-Li Tseng¹, Kai S Erdmann³

Affiliations

¹ Department of Biomedical Science & Centre of Membrane Interactions and Dynamics, University of Sheffield, Sheffield, S10 2TN, UK.
² Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
³ Department of Biomedical Science & Centre of Membrane Interactions and Dynamics, University of Sheffield, Sheffield, S10 2TN, UK. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigens, Neoplasm / analysis
Antigens, Neoplasm / metabolism
Antigens, Neoplasm / physiology*
Apoptosis
Dysbindin / metabolism
Endocytosis / physiology*
Fas Ligand Protein / analysis
Fas Ligand Protein / metabolism
HeLa Cells
Humans
Intracellular Signaling Peptides and Proteins / analysis
Intracellular Signaling Peptides and Proteins / metabolism
Intracellular Signaling Peptides and Proteins / physiology*
Protein Tyrosine Phosphatase, Non-Receptor Type 13 / analysis
Protein Tyrosine Phosphatase, Non-Receptor Type 13 / metabolism
Protein Tyrosine Phosphatase, Non-Receptor Type 13 / physiology
Signal Transduction
Vesicular Transport Proteins / analysis
Vesicular Transport Proteins / metabolism
Vesicular Transport Proteins / physiology*
fas Receptor / analysis
fas Receptor / metabolism

Substances

Antigens, Neoplasm
Dysbindin
ENTR1 protein, human
Fas Ligand Protein
Intracellular Signaling Peptides and Proteins
Vesicular Transport Proteins
fas Receptor
PTPN13 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 13