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

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2015 Oct 22

PMID 26488816

Citations 68

Authors

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

Affiliations

Soon will be listed here.

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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