Phosphorylation of iRhom2 at the plasma membrane controls mammalian TACE-dependent inflammatory and growth factor signalling

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Abstract

Proteolytic cleavage and release from the cell surface of membrane-tethered ligands is an important mechanism of regulating intercellular signalling. TACE is a major shedding protease, responsible for the liberation of the inflammatory cytokine TNFα and ligands of the epidermal growth factor receptor. iRhoms, catalytically inactive members of the rhomboid-like superfamily, have been shown to control the ER-to-Golgi transport and maturation of TACE. Here, we reveal that iRhom2 remains associated with TACE throughout the secretory pathway, and is stabilised at the cell surface by this interaction. At the plasma membrane, ERK1/2-mediated phosphorylation and 14-3-3 protein binding of the cytoplasmic amino-terminus of iRhom2 alter its interaction with mature TACE, thereby licensing its proteolytic activity. We show that this molecular mechanism is responsible for triggering inflammatory responses in primary mouse macrophages. Overall, iRhom2 binds to TACE throughout its lifecycle, implying that iRhom2 is a primary regulator of stimulated cytokine and growth factor signalling.

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Adam Graham Grieve

Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

Competing interests
No competing interests declared.
Hongmei Xu

Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

Competing interests
No competing interests declared.
Ulrike Künzel

Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

Competing interests
No competing interests declared.
Paul Bambrough

Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

Competing interests
No competing interests declared.
Boris Sieber

Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

Competing interests
No competing interests declared.
Matthew Freeman

Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

For correspondence
matthew.freeman@path.ox.ac.uk

Competing interests
Matthew Freeman, Reviewing editor, <i>eLife</i>.

"This ORCID iD identifies the author of this article:" 0000-0003-0410-5451

Funding

Wellcome (101035/Z/13/Z)

Adam Graham Grieve
Hongmei Xu
Ulrike Künzel
Paul Bambrough
Boris Sieber
Matthew Freeman

Medical Research Council (Graduate student scholarship)

Ulrike Künzel

Boehringer Ingelheim Fonds (Graduate student scholarship)

Ulrike Künzel
Boris Sieber

National Natural Science Foundation of China (31640023)

Hongmei Xu

Horizon 2020 Framework Programme (Marie Sklodowska-Curie grant agreement 659166)

Adam Graham Grieve

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with University of Oxford and UK Government rules and guidelines. The procedures and justification for the research was approved under UK PPL 80/2584.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.