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.
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.
Zhifang
Z
Cao
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.
Kara L
KL
Conway
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.
Robert J
RJ
Heath
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jason S
JS
Rush
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Elizaveta S
ES
Leshchiner
Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Zaida G
ZG
Ramirez-Ortiz
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.
Natalia B
NB
Nedelsky
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.
Hailiang
H
Huang
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.
Aylwin
A
Ng
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.
Agnès
A
Gardet
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, Nijmegen 6525 GA, the Netherlands.
Shih-Chin
SC
Cheng
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Alykhan F
AF
Shamji
Research Center, Montreal Heart Institute and Université de Montréal, QC H1T 1C8, Canada.
John D
JD
Rioux
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen T9700 RB, the Netherlands.
Cisca
C
Wijmenga
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Nijmegen Medical Center, Nijmegen 6525 GA, the Netherlands.
Mihai G
MG
Netea
Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Terry K
TK
Means
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.
Mark J
MJ
Daly
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.
Ramnik J
RJ
Xavier
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D058365:Candidiasis, Invasive / Q000235:genetics / Q000276:immunology*; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011945:Receptors, Angiotensin / Q000737:chemistry / Q000172:deficiency / Q000502:physiology*; D017466:Receptors, Endothelin / Q000737:chemistry / Q000172:deficiency / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000502:physiology*; D054875:Ubiquitination
D000276:Adjuvants, Immunologic; D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; C513280:Card9 protein, mouse; D016207:Cytokines; C510877:Dear1 protein, mouse; D020033:Protein Isoforms; D011945:Receptors, Angiotensin; D017466:Receptors, Endothelin; D011993:Recombinant Fusion Proteins; D000070584:Tripartite Motif Proteins; C583162:TRIM62 protein, human; D044767:Ubiquitin-Protein Ligases