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

Immunity
Authors
Keywords
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.

Year of Publication
2015
Journal
Immunity
Volume
43
Issue
4
Pages
715-26
Date Published
2015 Oct 20
ISSN
1097-4180
DOI
10.1016/j.immuni.2015.10.005
PubMed ID
26488816
PubMed Central ID
PMC4672733
Links
Grant list
RC1 DK086502 / DK / NIDDK NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
R01 AI084884 / AI / NIAID NIH HHS / United States
AI084884 / AI / NIAID NIH HHS / United States
U01 DK062432 / DK / NIDDK NIH HHS / United States
AR066716 / AR / NIAMS NIH HHS / United States
K01 AR066716 / AR / NIAMS NIH HHS / United States
DK086502 / DK / NIDDK NIH HHS / United States
DK097485 / DK / NIDDK NIH HHS / United States
DK062432 / DK / NIDDK NIH HHS / United States
R01 DK097485 / DK / NIDDK NIH HHS / United States