Author
Niovi Setta-Kaffetzi
Bio: Niovi Setta-Kaffetzi is an academic researcher from King's College London. The author has contributed to research in topics: Gene silencing & 5-HT5A receptor. The author has an hindex of 5, co-authored 5 publications receiving 403 citations.
Papers
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TL;DR: It is found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling.
Abstract: Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit σ1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll-like receptor homeostasis.
147 citations
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140 citations
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King's College London1, University of Glasgow2, Children's of Alabama3, Boston Children's Hospital4, University of Szeged5, University of Freiburg6, National Skin Centre7, Royal Prince Alfred Hospital8, Helsinki University Central Hospital9, Radboud University Nijmegen Medical Centre10, Hebron University11, University Hospital Galway12, University of Manchester13, Francis Crick Institute14
TL;DR: It is shown that keratinocytes play a key role in skin autoinflammation and autophagy modulation of IL-36 signaling as a therapeutic target, and the effects of gene silencing on this pathway are investigated.
121 citations
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6 citations
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TL;DR: A number of cytokines have been therapeutically targeted with success, revolutionizing treatment of this disease and are reviewed here to suggest potential therapeutic targets.
306 citations
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TL;DR: Physicians' knowledge is essential to the improvement of diagnosis and management, and in the limitation and prevention of long-term sequelae.
289 citations
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TL;DR: In this paper, the pathogenesis of psoriasis can be explained by dysregulation of immunological cell function as well as keratinocyte proliferation/differentiation, and it has been demonstrated that Th17 cells play a key role.
Abstract: The pathogenesis of psoriasis can be explained by dysregulation of immunological cell function as well as keratinocyte proliferation/differentiation. Recently, the immunological pathomechanism has been clarified substantially. Whereas T-helper (Th)1 overactivation was thought to induce occurrence of psoriasis, it has been demonstrated that Th17 cells play a key role. Th17 development is maintained by interleukin (IL)-23 mainly produced by dendritic cells. Th17 cells produce various cytokines, including IL-17A, IL-17F and IL-22. IL-17A and IL-22 induce not only keratinocyte proliferation, but also tumor necrosis factor (TNF)-α, chemokine (C-X-C motif) ligand (CXCL)1 and CXCL8 production. TNF-α accelerates the infiltration of inflammatory cells, including lymphocytes, monocytes and neutrophils, from the peripheral blood into skin with dendritic cell activation. In addition, antimicrobial peptides are overexpressed in psoriatic skin lesions, and the antimicrobial peptide, LL-37, activates dendritic cells, which leads to the development of inflammation. Furthermore, activation of nuclear factor-κB signal induces the expression of keratins 6 and 16 in keratinocytes, which are associated with acanthosis and reduced turnover time in the epidermis. The progression of the pathomechanism contributes to the development of new therapies for psoriasis.
284 citations
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TL;DR: The purification of coated vesicles and the discovery of clathrin by Barbara Pearse in 1975 was a landmark in cell biology, but there are still a number of unanswered questions, including howClathrin‐mediated trafficking is regulated and how the machinery evolved.
Abstract: The purification of coated vesicles and the discovery of clathrin by Barbara Pearse in 1975 was a landmark in cell biology. Over the past 40 years, work from many labs has uncovered the molecular details of clathrin and its associated proteins, including how they assemble into a coated vesicle and how they select cargo. Unexpected connections have been found with signalling, development, neuronal transmission, infection, immunity and genetic disorders. But there are still a number of unanswered questions, including how clathrin-mediated trafficking is regulated and how the machinery evolved.
272 citations
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TL;DR: GPP alone is a distinct subtype of GPP and is etiologically distinguished from GPP with PV, and that the majority of G PP alone is caused by deficiency of the interleukin-36 receptor antagonist due to IL36RN mutations.
263 citations