UBAC1/KPC2 Regulates TLR3 Signaling in Human Keratinocytes through Functional Interaction with the CARD14/CARMA2sh-TANK Complex

Int J Mol Sci. 2020 Dec 9;21(24):9365. doi: 10.3390/ijms21249365.

Abstract

CARD14/CARMA2 is a scaffold molecule whose genetic alterations are linked to human inherited inflammatory skin disorders. However, the mechanisms through which CARD14/CARMA2 controls innate immune response and chronic inflammation are not well understood. By means of a yeast two-hybrid screening, we identified the UBA Domain Containing 1 (UBAC1), the non-catalytic subunit of the E3 ubiquitin-protein ligase KPC complex, as an interactor of CARMA2sh, the CARD14/CARMA2 isoform mainly expressed in human keratinocytes. UBAC1 participates in the CARMA2sh/TANK complex and promotes K63-linked ubiquitination of TANK. In human keratinocytes, UBAC1 negatively regulates the NF-κF-activating capacity of CARMA2sh following exposure to poly (I:C), an agonist of Toll-like Receptor 3. Overall, our data indicate that UBAC1 participates in the inflammatory signal transduction pathways involving CARMA2sh.

Keywords: BCL10; CARD14; CARMA2sh; NF-κB; TANK; UBAC1; Ubiquitin; psoriasis.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • CARD Signaling Adaptor Proteins / metabolism*
  • Guanylate Cyclase / metabolism*
  • HEK293 Cells
  • HaCaT Cells
  • Humans
  • Membrane Proteins / metabolism*
  • NF-kappa B / metabolism
  • Protein Binding
  • Signal Transduction
  • Toll-Like Receptor 3 / metabolism
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • CARD Signaling Adaptor Proteins
  • Membrane Proteins
  • NF-kappa B
  • TANK protein, human
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • UBAC1 protein, human
  • Ubiquitin-Protein Ligases
  • CARD14 protein, human
  • Guanylate Cyclase