title: AKT1-mediated Lamin A/C degradation is required for nuclear degradation and normal epidermal terminal differentiation.
abstract: Nuclear degradation is a key stage in keratinocyte terminal differentiation and the formation of the cornified envelope that comprises the majority of epidermal barrier function. Parakeratosis, the retention of nuclear material in the cornified layer of the epidermis, is a common histological observation in many skin diseases, notably in atopic dermatitis and psoriasis. Keratinocyte nuclear degradation is not well characterised, and it is unclear whether the retained nuclei contribute to the altered epidermal differentiation seen in eczema and psoriasis. Loss of AKT1 function strongly correlated with parakeratosis both in eczema samples and in organotypic culture models. Although levels of DNAses, including DNase1L2, were unchanged, proteomic analysis revealed an increase in Lamin A/C. AKT phosphorylates Lamin A/C, targeting it for degradation. Consistent with this, Lamin A/C degradation was inhibited and Lamin A/C was observed in the cornified layer of AKT1 knockdown organotypic cultures, surrounding retained nuclear material. Using AKT-phosphorylation-dead Lamin A constructs we show that the retention of nuclear material is sufficient to cause profound changes in epidermal terminal differentiation, specifically a reduction in Loricrin, Keratin 1, Keratin 10, and filaggrin expression. We show that preventing nuclear degradation upregulates BMP2 expression and SMAD1 signalling. Consistent with these data, we observe both parakeratosis and evidence of increased SMAD1 signalling in atopic dermatitis. We therefore present a model that, in the absence of AKT1-mediated Lamin A/C degradation, DNA degradation processes, such as those mediated by DNAse 1L2, are prevented, leading to parakeratosis and changes in epidermal differentiation.
authors.affiliation: Immunobiology and Dermatology, UCL Institute of Child Health, London, UK.|Livingstone Skin Research Centre, UCL Institute of Child Health, London, UK.
authors.forename: A S
authors.initials: AS
authors.lastname: Naeem
authors.affiliation: Immunobiology and Dermatology, UCL Institute of Child Health, London, UK.|Livingstone Skin Research Centre, UCL Institute of Child Health, London, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Immunobiology and Dermatology, UCL Institute of Child Health, London, UK.|Livingstone Skin Research Centre, UCL Institute of Child Health, London, UK.
authors.forename: W L
authors.initials: WL
authors.lastname: Di
authors.affiliation: Department of Surgery, Medicine and Dentistry, Università degli Studi di Modena e Reggio Emilia, Modena, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Marmiroli
authors.affiliation: Immunobiology and Dermatology, UCL Institute of Child Health, London, UK.|Livingstone Skin Research Centre, UCL Institute of Child Health, London, UK.
authors.forename: R F L
authors.initials: RF
authors.lastname: O'Shaughnessy
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002454:Cell Differentiation; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D053556:Keratin-1 / Q000235:genetics / Q000378:metabolism; D053550:Keratin-10 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D034904:Lamin Type A / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D053556:Keratin-1; D034904:Lamin Type A; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D051898:Smad1 Protein; C064554:loricrin; D053550:Keratin-10; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt