The Skin Barrier Defects Caused by KeratinocyteSpecific Deletion of ADAM17 or EGFR are Based on Highly Similar Proteome and Degradome Alteration
Authors
Stefan Tholen, Cristina Wolf, Bettina Mayer, Julia Daniela Knopf, Stefanie Löffek, Yawen Qian, Jayachandran N Kizhakkedathu, Martin L. Biniossek, Claus-Werner Franzke, and Oliver Schilling
Institution
University of Freiburg
Country
Germany
Year
2016
Journal
Journal of Proteome Research
Abstract
Keratinocyte-specific deletion of ADAM17 in mice impairs terminal differentiation of keratinocytes
leading to severe epidermal barrier defects. Mice deficient for ADAM17 in keratinocytes phenocopy
mice with a keratinocyte-specific deletion of EGFR, highlighting the role of ADAM17 as a “ligand
sheddase” of EGFR ligands.
In this study we aim for the first proteomic / degradomic approach to characterize the disruption of
the ADAM17-EGFR signaling axis and its consequences for epidermal barrier formation.
Proteomic profiling of the epidermal proteome of mice deficient for either ADAM17 or EGFR in
keratinocytes at postnatal days 3 and 10 revealed highly similar protein alterations for ADAM17
and EGFR deficiency. These include massive proteome alterations of structural and regulatory
components important for barrier formation, like transglutaminases, involucrin, filaggrin, and
filaggrin-2. Cleavage site analysis using TAILS revealed increased proteolytic processing of S100
fused-type proteins, including filaggrin-2. Alterations in proteolytic processing are supported by
altered abundance of numerous proteases upon keratinocyte-specific Adam17 or Egfr deletion,
among them kallikreins, cathepsins and their inhibitors.
This study highlights the essential role of proteolytic processing for maintenance of a functional
epidermal barrier. Furthermore it suggests that most defects in formation of the postnatal
epidermal barrier upon keratinocyte-specific ADAM17 deletion are mediated via EGFR