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Immunity DOI:10.1016/j.immuni.2015.10.005

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

Publication TypeJournal Article
Year of Publication2015
AuthorsCao, Z, Conway, KL, Heath, RJ, Rush, JS, Leshchiner, ES, Ramirez-Ortiz, ZG, Nedelsky, NB, Huang, H, Ng, A, Gardet, A, Cheng, S-C, Shamji, AF, Rioux, JD, Wijmenga, C, Netea, MG, Means, TK, Daly, MJ, Xavier, RJ
JournalImmunity
Volume43
Issue4
Pages715-26
Date Published2015 Oct 20
ISSN1097-4180
KeywordsAdjuvants, Immunologic, Animals, Candidiasis, Invasive, CARD Signaling Adaptor Proteins, 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, Tripartite Motif Proteins, Ubiquitin-Protein Ligases, Ubiquitination
Abstract

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.

DOI10.1016/j.immuni.2015.10.005
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/26488816?dopt=Abstract

Alternate JournalImmunity
PubMed ID26488816
PubMed Central IDPMC4672733
Grant ListRC1 DK086502 / DK / NIDDK NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
R01 AI084884 / AI / NIAID NIH HHS / United States
AI084884 / AI / NIAID NIH HHS / United States
U01 DK062432 / DK / NIDDK NIH HHS / United States
AR066716 / AR / NIAMS NIH HHS / United States
K01 AR066716 / AR / NIAMS NIH HHS / United States
DK086502 / DK / NIDDK NIH HHS / United States
DK097485 / DK / NIDDK NIH HHS / United States
DK062432 / DK / NIDDK NIH HHS / United States
R01 DK097485 / DK / NIDDK NIH HHS / United States