AP1S3 mutations cause skin autoinflammation by disrupting keratinocyte autophagy and up-regulating IL-36 production

Satveer K. Mahil, Sophie Twelves, Katalin Farkas, Niovi Setta-Kaffetzi, A David Burden, Joanna E. Gach, Alan D. Irvine, László Képíró, Maja Mockenhaupt, Hazel H. Oon, Jason Pinner, Annamari Ranki, Marieke MB. Seyger, Pere Soler-Palacin, Eoin R. Storan, Eugene S. Tan, Laurence Valeyrie-Allanore, Helen S. Young, Richard C. Trembath, Siew-Eng ChoonMarta Szell, Zsuzsanna Bata-Csorgo, Catherine H. Smith, Paola Di Meglio, Jonathan N. Barker, Francesca Capon

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121 Citations (Scopus)
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Prominent skin involvement is a defining characteristic of autoinflammatory disorders (AID) caused by abnormal IL-1 signalling. However, the pathways and cell types that drive cutaneous AID features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of AID with predominant cutaneous manifestations. We specifically characterised 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 demonstrated that AP1S3 expression is distinctively elevated in keratinocytes. Since 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 demonstrated that as a consequence, AP1S3 deficient cells up-regulate IL-1 signalling and over-express 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 demonstrate that keratinocytes play a key role in skin autoinflammation and identify autophagy modulation of IL-36 signalling as a therapeutic target.
Original languageEnglish
Pages (from-to)2251–2259
JournalJournal of Investigative Dermatology
Issue number11
Early online date5 Jul 2016
Publication statusPublished - 30 Nov 2016


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