Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation.

CARD9 is a central component of anti-fungal innate immune signaling via C-type lectin receptors, and several immune-related disorders are associated with CARD9 alterations. Here, we used a rare CARD9 variant that confers protection against inflammatory bowel disease as an entry point to investigating CARD9 regulation. We showed that the protective ...
variant of CARD9, which is C-terminally truncated, acted in a dominant-negative manner for CARD9-mediated cytokine production, indicating an important role for the C terminus in CARD9 signaling. We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity. Furthermore, we showed that similar to Card9-deficient mice, Trim62-deficient mice had increased susceptibility to fungal infection. In this study, we utilized a rare protective allele to uncover a TRIM62-mediated mechanism for regulation of CARD9 activation.
Mesh Terms:
Adjuvants, Immunologic, Animals, CARD Signaling Adaptor Proteins, Candidiasis, Invasive, Colitis, Cytokines, Dendritic Cells, Genes, Dominant, Genetic Predisposition to Disease, HEK293 Cells, HeLa Cells, Humans, Inflammatory Bowel Diseases, Mice, Mice, 129 Strain, Mice, Knockout, Protein Interaction Mapping, Protein Isoforms, Protein Processing, Post-Translational, Protein Structure, Tertiary, Receptors, Angiotensin, Receptors, Endothelin, Recombinant Fusion Proteins, Signal Transduction, Specific Pathogen-Free Organisms, Ubiquitin-Protein Ligases, Ubiquitination
Immunity
Date: Oct. 20, 2015
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