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Cell Death Dis. 2018 Apr 1;9(4):412. doi: 10.1038/s41419-018-0407-2.

Orchestrated control of filaggrin-actin scaffolds underpins cornification.

Author information

1
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.
2
Institute of Biotechnology UG, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, 80-307, Gdańsk, Poland.
3
Research Complex at Harwell, Central Laser Facility, Rutherford Appleton Laboratory Science and Technology Facilities Council, Harwell-Oxford, Didcot, OX11 0FA, UK.
4
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford, OX3 7FY, UK.
5
Immunobiology, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
6
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106, Warsaw, Poland.
7
Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK.
8
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK. christian.eggeling@rdm.ox.ac.uk.
9
Institute of Applied Optics, Friedrich-Schiller-University Jena, Max-Wien Platz 4, 07743, Jena, Germany. christian.eggeling@rdm.ox.ac.uk.
10
Leibniz Institute of Photonic Technology e.V., Albert-Einstein-Straße 9, 07745, Jena, Germany. christian.eggeling@rdm.ox.ac.uk.
11
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK. graham.ogg@ndm.ox.ac.uk.

Abstract

Epidermal stratification critically depends on keratinocyte differentiation and programmed death by cornification, leading to formation of a protective skin barrier. Cornification is dynamically controlled by the protein filaggrin, rapidly released from keratohyalin granules (KHGs). However, the mechanisms of cornification largely remain elusive, partly due to limitations of the observation techniques employed to study filaggrin organization in keratinocytes. Moreover, while the abundance of keratins within KHGs has been well described, it is not clear whether actin also contributes to their formation or fate. We employed advanced (super-resolution) microscopy to examine filaggrin organization and dynamics in skin and human keratinocytes during differentiation. We found that filaggrin organization depends on the cytoplasmic actin cytoskeleton, including the role for α- and β-actin scaffolds. Filaggrin-containing KHGs displayed high mobility and migrated toward the nucleus during differentiation. Pharmacological disruption targeting actin networks resulted in granule disintegration and accelerated cornification. We identified the role of AKT serine/threonine kinase 1 (AKT1), which controls binding preference and function of heat shock protein B1 (HspB1), facilitating the switch from actin stabilization to filaggrin processing. Our results suggest an extended model of cornification in which filaggrin utilizes actins to effectively control keratinocyte differentiation and death, promoting epidermal stratification and formation of a fully functional skin barrier.

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