Author(s):
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Cao, Z.; Conway, K.L.; Heath, R.J.; Rush, J.S.; Leshchiner, E.S.; Ramirez-Ortiz, Z.G.; Nedelsky, N.B.; Huang, H.; Ng, A.; Gardet, A.; Cheng, S.C.; Shamji, A.F.; Rioux, J.D.; Wijmenga, C.;
Netea, M.G.
; Means, T.K.; Daly, M.J.; Xavier, R.J.
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Subject:
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Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences |
Abstract:
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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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