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

Area of Science:

• Immunology
• Cell Biology
• Dermatology

Background:

• The CARMA/BCL10/MALT1 (CBM) complex is key to NF-κB transcription factor activation.
• Missense mutations in CARMA2sh are linked to dominant, highly penetrant psoriasis.
• CARMA2sh's role in keratinocyte signaling from pathogen recognition to NF-κB activation is under investigation.

Purpose of the Study:

• To investigate the role of CARMA2sh in human keratinocytes' NF-κB signaling pathway.
• To identify regulatory mechanisms of CARMA2sh, particularly concerning psoriasis-associated mutations.
• To explore potential therapeutic strategies for skin disorders by targeting CARMA2sh-mediated signaling.

Main Methods:

• Utilized human keratinocytes to study CARMA2sh function.
• Investigated the interaction and phosphorylation of CARMA2sh by ULK2.
• Analyzed the effect of psoriasis-linked CARMA2sh mutants on NF-κB activation.
• Employed a peptide to block CARD-mediated BCL10 interactions.

Main Results:

• CARMA2sh is essential for NF-κB activation in keratinocytes upon pathogen-associated molecular pattern recognition.
• ULK2 kinase binds and phosphorylates CARMA2sh, inhibiting NF-κB signaling via BCL10 lysosomal degradation.
• Psoriasis-associated CARMA2sh mutants evade ULK2-mediated inhibition.
• A peptide blocking CARD-mediated BCL10 interactions diminishes the NF-κB activating capacity of psoriasis-linked CARMA2sh mutants.

Conclusions:

• A novel signaling pathway involving ULK2 regulation of CARMA2sh in keratinocytes is elucidated.
• Dysregulation of this pathway, particularly CARMA2sh mutations, contributes to psoriasis pathogenesis.
• Targeting CARMA2sh-BCL10 interactions presents a potential therapeutic avenue for skin disorders like psoriasis.