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

被引：116

作者：

Cao, Zhifang ^{[1
,2
,3
,4
]}

Conway, Kara L. ^{[1
,2
,3
,4
,5
]}

Heath, Robert J. ^{[1
,2
,3
,4
,5
]}

Rush, Jason S. ^{[5
]}

Leshchiner, Elizaveta S. ^{[5
]}

Ramirez-Ortiz, Zaida G. ^{[6
,7
,8
]}

Nedelsky, Natalia B. ^{[1
,2
,3
,4
]}

Huang, Hailiang ^{[3
,5
,9
]}

Ng, Aylwin ^{[1
,2
,3
,4
,5
]}

Gardet, Agnes ^{[1
,2
,3
,4
]}

Cheng, Shih-Chin ^{[10
,11
]}

Shamji, Alykhan F. ^{[5
]}

Rioux, John D. ^{[12
,13
]}

Wijmenga, Cisca ^{[14
]}

Netea, Mihai G. ^{[10
,11
]}

Means, Terry K. ^{[6
,7
,8
]}

Daly, Mark J. ^{[3
,5
,9
]}

Xavier, Ramnik J. ^{[1
,2
,3
,4
,5
]}

机构：

[1] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA

[3] Harvard Univ, Sch Med, Boston, MA 02114 USA

[4] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA

[5] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[6] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA

[7] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Charlestown, MA 02129 USA

[8] Harvard Univ, Sch Med, Charlestown, MA 02129 USA

[9] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[10] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands

[11] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis, NL-6525 GA Nijmegen, Netherlands

[12] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada

[13] Univ Montreal, Montreal, PQ H1T 1C8, Canada

[14] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands

来源：

IMMUNITY | 2015年 / 43卷 / 04期

关键词：

INHERITED CARD9 DEFICIENCY; INNATE IMMUNITY; SUSCEPTIBILITY LOCI; ANTIVIRAL RESPONSE; CROHNS-DISEASE; FAMILY; RECOGNITION; INFECTION; PROTEINS; CELLS;

D O I：

10.1016/j.immuni.2015.10.005

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：715 / 726

页数：12

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