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

  • Immunity. 2015 Oct 20;43(4):715-26. doi: 10.1016/j.immuni.2015.10.005.
Zhifang Cao  1 ,  Kara L Conway  2 ,  Robert J Heath  2 ,  Jason S Rush  3 ,  Elizaveta S Leshchiner  3 ,  Zaida G Ramirez-Ortiz  4 ,  Natalia B Nedelsky  1 ,  Hailiang Huang  5 ,  Aylwin Ng  2 ,  Agnès Gardet  1 ,  Shih-Chin Cheng  6 ,  Alykhan F Shamji  3 ,  John D Rioux  7 ,  Cisca Wijmenga  8 ,  Mihai G Netea  6 ,  Terry K Means  4 ,  Mark J Daly  5 ,  Ramnik J Xavier  9
Affiliations
  • 1. Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • 2. Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 3. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 4. Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
  • 5. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • 6. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, Nijmegen 6525 GA, the Netherlands.
  • 7. Research Center, Montreal Heart Institute and Université de Montréal, QC H1T 1C8, Canada.
  • 8. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen T9700 RB, the Netherlands.
  • 9. Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: [email protected].
PMID: 26488816 DOI: 10.1016/j.immuni.2015.10.005
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.