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

Zhifang Cao, Kara L. Conway, Robert J. Heath, Jason S. Rush, Elizaveta S. Leshchiner, Zaida G. Ramirez-Ortiz, Natalia B. Nedelsky, Hailiang Huang, Aylwin Ng, Agnes Gardet, Shih-Chin Cheng, Alykhan F. Shamji, John D. Rioux, Cisca Wijmenga, Mihai G. Netea, Terry K. Means, Mark J. Daly, Ramnik J. Xavier*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

53 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)715-726
Number of pages12
JournalImmunity
Volume43
Issue number4
DOIs
Publication statusPublished - 20-Oct-2015

Keywords

  • INHERITED CARD9 DEFICIENCY
  • COLITIS SUSCEPTIBILITY LOCI
  • INNATE IMMUNITY
  • BOWEL-DISEASE
  • ANTIVIRAL RESPONSE
  • DEEP DERMATOPHYTOSIS
  • FUNGAL-INFECTIONS
  • CANDIDA-ALBICANS
  • DENDRITIC CELLS
  • CROHNS-DISEASE

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