CARMA2sh and ULK2 control pathogen-associated molecular patterns recognition in human keratinocytes: psoriasis-linked CARMA2sh mutants escape ULK2 censorship

Scudiero, Ivan; Mazzone, P.; D’Andrea, Luca E.; Ferravante, Angela; Zotti, Tiziana; Telesio, Gianluca; Rubis, Gabriele De; Reale, Carla; Pizzulo, Maddalena; Shanmugakonar, Muralitharan; Vito, Pasquale; Stilo, Romania

doi:10.1038/cddis.2017.51

Cited by 12 publications

(15 citation statements)

References 46 publications

(88 reference statements)

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“…To date, no correlation has been made between variant localisation and disease severity or age of onset. However, mutations in this area affect the ability of the molecule to maintain its autoinhibitory state ( 2 , 71 – 73 ).…”

Section: Inflammatory Skin Disorders Associated With Card14 Variantsmentioning

confidence: 99%

Clinical and Genetic Heterogeneity of CARD14 Mutations in Psoriatic Skin Disease

Israël

Mellett

2018

Front. Immunol.

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The CARD: BCL10: MALT1 (CBM) complex is an essential signaling node for maintaining both innate and adaptive immune responses. CBM complex components have gained considerable interest due to the dramatic effects of associated mutations in causing severe lymphomas, immunodeficiencies, carcinomas and inflammatory disease. While MALT1 and BCL10 are ubiquitous proteins, the CARD-containing proteins differ in their tissue expression. CARD14 is primarily expressed in keratinocytes. The CARD14-BCL10-MALT1 complex is activated by upstream pathogen-associated molecular pattern-recognition in vitro, highlighting a potentially crucial role in innate immune defense at the epidermal barrier. Recent findings have demonstrated how CARD14 orchestrates activation of the NF-κB and MAPK signaling pathways via recruitment of BCL10 and MALT1, leading to the upregulation of pro-inflammatory genes encoding IL-36γ, IL-8, Ccl20 and anti-microbial peptides. Following the identification of CARD14 gain-of function mutations as responsible for the psoriasis susceptibility locus PSORS2, the past years have witnessed a large volume of case reports and association studies describing CARD14 variants as causal or predisposing to a wide range of inflammatory skin disorders. Recent publications of mouse models also helped to better understand the physiological contribution of CARD14 to psoriasis pathogenesis. In this review, we summarize the clinical, genetic and functional aspects of human and murine CARD14 mutations and their contribution to psoriatic disease pathogenesis.

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Section: Inflammatory Skin Disorders Associated With Card14 Variantsmentioning

confidence: 99%

Clinical and Genetic Heterogeneity of CARD14 Mutations in Psoriatic Skin Disease

Israël

Mellett

2018

Front. Immunol.

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“…Both ULK2 and RNF7 are indeed able to repress CARMA2 sh -induced NF-κB activation, although through different mechanisms. In particular, ULK2 phosphorylates CARMA2 sh and promotes lysosomal degradation of BCL10, whereas RNF7 alters the ubiquitination state of MALT1 and NEMO ( 58 , 59 ). Intriguingly, a protein similar to RNF7, named RNF181, has been identified as an interactor of CARMA1 and functions as an E3 ubiquitin ligase to inhibit antigen receptor signaling to NF-κB downstream of CARMA1 ( 60 ).…”

Section: Carma2 Signalingmentioning

confidence: 99%

“…Recent evidence indicates that CARMA2 sh and MALT1 play a role in the signal transduction pathway that connects pathogen-associated molecular patterns recognition to NF-κB activation ( 57 , 58 ). Microorganisms, such as bacterial and fungi cells display in fact pathogen-associated molecular patterns (PAMPs), which are molecules associated with groups of pathogens, and activate NF-κB upon agonistic binding to Pattern Recognition Receptors, including members of the Toll-like receptors (TLR) family expressed on human keratinocytes.…”

Section: Carma2 Signalingmentioning

confidence: 99%

“…Microorganisms, such as bacterial and fungi cells display in fact pathogen-associated molecular patterns (PAMPs), which are molecules associated with groups of pathogens, and activate NF-κB upon agonistic binding to Pattern Recognition Receptors, including members of the Toll-like receptors (TLR) family expressed on human keratinocytes. Indeed, depletion of each of the components of the CBM complex significantly impairs expression of NF-κB target genes in human epithelia keratinocytes exposed to heat-killed Escherichia coli, Sthaphylococcus aureus or Candida valida ( 58 ). Altogether, these findings strengthen the existence of a causal link between microbial infections and the onset of psoriasis and encourage more efforts in further clarifying how exposure to PAMPs could determine disruption of skin homeostasis, inflammation and hyperproliferation in susceptible keratinocytes.…”

Section: Carma2 Signalingmentioning

confidence: 99%

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CARD14/CARMA2 Signaling and its Role in Inflammatory Skin Disorders

et al. 2018

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CARMA proteins represent a family of scaffold molecules which play several crucial biological functions, including regulation of immune response and inflammation, tissue homeostasis, and modulation of G-Protein Coupled Receptor (GPCR) signaling. Among the CARMA proteins, CARD14/CARMA2 and its alternatively spliced isoforms are specifically expressed in epithelial cells and keratinocytes. Recent evidences have shown that CARD14/CARMA2 mediates induction of inflammatory response in keratinocytes, and that mutations in CARD14/CARMA2 gene segregate with familial transmission of chronic inflammatory disorders of the human skin. Similarly to CARD11/CARMA1 and CARD10/CARMA3, CARD14/CARMA2 signaling occurs trough formation of a trimeric complex which includes BCL10 and MALT1 proteins. However, it is becoming increasingly evident that in addition to the CBM complex components, a number of accessory molecules are able to finely modulate the signals conveyed on and amplified by CARD14/CARMA2. The study of these molecules is important both to understand the molecular mechanisms that underlie the role of CARMA2 in keratinocytes and because they represent potential therapeutic targets for the development of therapeutic strategies aiming at the treatment of inflammatory diseases of the human skin. In this review, we provide an overview on the molecular mechanisms mediating CARD14/CARMA2 signaling and its implication in our understanding of the pathogenesis of human inflammatory skin disorders.

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“…CARD14 was recently described to be activated in vitro in response to zymosan and Staphylococcus aureus pathogenassociated molecular pattern agonists (Schmitt et al, 2016;Scudiero et al, 2017). Therefore, CARD14 likely plays its main role in innate immune defense, which is supported by the genes activated downstream of CARD14, which typically encode for proinflammatory cytokines and chemokines, including IL-36g, IL-8, and Ccl20 (Jordan, 2012a).…”

Section: Introductionmentioning

confidence: 99%

993 CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo

Mellett

Meier

Mohanan

et al. 2018

Journal of Investigative Dermatology

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Rare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule CARD14, have been associated with an increased susceptibility to psoriasis, but the physiological impact of CARD14 gain-offunction mutations remains to be fully determined in vivo. Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14DE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis, and immune cell infiltration. Affected skin of these mice is characterized by elevated expression of anti-microbial peptides, chemokines, and cytokines (including T helper type 17 cell-signature cytokines) and an immune infiltrate rich in neutrophils, myeloid cells, and T cells, reminiscent of human psoriatic skin. Disease pathogenesis was driven by the IL-23/IL-17 axis, and neutralization of IL-23p19, the key cytokine in maintaining T helper type 17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and proinflammatory cytokines. Therefore, hyperactivation of CARD14 alone is sufficient to orchestrate the complex immunopathogenesis that drives T helper type 17-mediated psoriasis skin disease in vivo.

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CARMA2sh and ULK2 control pathogen-associated molecular patterns recognition in human keratinocytes: psoriasis-linked CARMA2sh mutants escape ULK2 censorship

Cited by 12 publications

References 46 publications

Clinical and Genetic Heterogeneity of CARD14 Mutations in Psoriatic Skin Disease

Clinical and Genetic Heterogeneity of CARD14 Mutations in Psoriatic Skin Disease

CARD14/CARMA2 Signaling and its Role in Inflammatory Skin Disorders

993 CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo

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