2. Academic Validation
  3. Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation

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

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: xavier@molbio.mgh.harvard.edu.
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.

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