title: AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production.
abstract: Prominent skin involvement is a defining characteristic of autoinflammatory disorders caused by abnormal IL-1 signaling. However, the pathways and cell types that drive cutaneous autoinflammatory features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of autoinflammatory disorders with predominant cutaneous manifestations. We specifically characterized the impact of mutations affecting AP1S3, a disease gene previously identified by our group and validated here in a newly ascertained patient resource. We first showed that AP1S3 expression is distinctively elevated in keratinocytes. Because AP1S3 encodes a protein implicated in autophagosome formation, we next investigated the effects of gene silencing on this pathway. We found that AP1S3 knockout disrupts keratinocyte autophagy, causing abnormal accumulation of p62, an adaptor protein mediating NF-κB activation. We showed that as a consequence, AP1S3-deficient cells up-regulate IL-1 signaling and overexpress IL-36α, a cytokine that is emerging as an important mediator of skin inflammation. These abnormal immune profiles were recapitulated by pharmacological inhibition of autophagy and verified in patient keratinocytes, where they were reversed by IL-36 blockade. These findings show that keratinocytes play a key role in skin autoinflammation and identify autophagy modulation of IL-36 signaling as a therapeutic target.
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: Satveer K
authors.initials: SK
authors.lastname: Mahil
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Twelves
authors.affiliation: MTA-SZTE Dermatological Research Group, Szeged, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Farkas
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: Niovi
authors.initials: N
authors.lastname: Setta-Kaffetzi
authors.affiliation: Department of Dermatology, University of Glasgow, Glasgow, UK.
authors.forename: A David
authors.initials: AD
authors.lastname: Burden
authors.affiliation: Department of Dermatology, Birmingham Children's Hospital, Birmingham, UK.
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Gach
authors.affiliation: Paediatric Dermatology, Our Lady's Children's Hospital, Dublin, Ireland.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Irvine
authors.affiliation: Department of Dermatology and Allergology, University of Szeged, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Képíró
authors.affiliation: Dokumentationszentrum schwerer Hautreaktionen (dZh) and RegiSCAR-study, Department of Dermatology, Medical Center-University of Freiburg, Freiburg, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Mockenhaupt
authors.affiliation: National Skin Centre, Singapore.
authors.forename: Hazel H
authors.initials: HH
authors.lastname: Oon
authors.affiliation: Department of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Pinner
authors.affiliation: Department of Skin and Allergic Diseases, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Annamari
authors.initials: A
authors.lastname: Ranki
authors.affiliation: Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Marieke M B
authors.initials: MMB
authors.lastname: Seyger
authors.affiliation: Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Soler-Palacin
authors.affiliation: Department of Dermatology, University Hospital, Galway, Ireland.
authors.forename: Eoin R
authors.initials: ER
authors.lastname: Storan
authors.affiliation: National Skin Centre, Singapore.
authors.forename: Eugene S
authors.initials: ES
authors.lastname: Tan
authors.affiliation: Department of Dermatology, Henri Mondor Hospital, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Valeyrie-Allanore
authors.affiliation: Department of Dermatology, University of Manchester.
authors.forename: Helen S
authors.initials: HS
authors.lastname: Young
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.affiliation: Department of Dermatology, Hospital Sultanah Aminah, Johor Bahru, Malaysia.
authors.forename: Siew-Eng
authors.initials: SE
authors.lastname: Choon
authors.affiliation: MTA-SZTE Dermatological Research Group, Szeged, Hungary; Institute of Medical Genetics, University of Szeged, Hungary.
authors.forename: Marta
authors.initials: M
authors.lastname: Szell
authors.affiliation: MTA-SZTE Dermatological Research Group, Szeged, Hungary; Department of Dermatology and Allergology, University of Szeged, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Bata-Csorgo
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Smith
authors.affiliation: Mill Hill Laboratory, The Francis Crick Institute, London, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Di Meglio
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London, UK.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Barker
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London, London, UK. Electronic address: francesca.capon@kcl.ac.uk.
authors.forename: Francesca
authors.initials: F
authors.lastname: Capon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D001343:Autophagy; D002460:Cell Line; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D011565:Psoriasis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007375:Interleukin-1; C572887:interleukin 36, human; D004247:DNA