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AP1S3 mutations cause skin autoinflammation by disrupting keratinocyte autophagy and up-regulating IL-36 production
journal contributionposted on 2020-08-20, 16:40 authored by 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 Choon, Marta Szell, Zsuzsanna Bata-Csorgo, Catherine H Smith, Paola Di Meglio, Jonathan N Barker, Francesca Capon
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.
Adaptor Proteins, Signal TransducingAgedAutophagyCell LineDNADNA Mutational AnalysisFemaleHumansInterleukin-1KeratinocytesMiddle AgedMutationPsoriasisSignal TransductionTranscriptional ActivationUp-RegulationStockinger FC0011591103 Clinical Sciences1112 Oncology and CarcinogenesisDermatology & Venereal Diseases