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

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

doi:10.1016/j.immuni.2015.10.005

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

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^*

^*Corresponding author for this work

Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	715-726
Number of pages	12
Journal	Immunity
Volume	43
Issue number	4
DOIs	https://doi.org/10.1016/j.immuni.2015.10.005
Publication status	Published - 20-Oct-2015

Keywords

INHERITED CARD9 DEFICIENCY
COLITIS SUSCEPTIBILITY LOCI
INNATE IMMUNITY
BOWEL-DISEASE
ANTIVIRAL RESPONSE
DEEP DERMATOPHYTOSIS
FUNGAL-INFECTIONS
CANDIDA-ALBICANS
DENDRITIC CELLS
CROHNS-DISEASE

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10.1016/j.immuni.2015.10.005

Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal ImmunityFinal publisher's version, 1.78 MBLicence: Elsevier

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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. (2015). Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation. Immunity, 43(4), 715-726. https://doi.org/10.1016/j.immuni.2015.10.005

Cao, Zhifang ; Conway, Kara L. ; Heath, Robert J. ; Rush, Jason S. ; Leshchiner, Elizaveta S. ; Ramirez-Ortiz, Zaida G. ; Nedelsky, Natalia B. ; Huang, Hailiang ; Ng, Aylwin ; Gardet, Agnes ; Cheng, Shih-Chin ; Shamji, Alykhan F. ; Rioux, John D. ; Wijmenga, Cisca ; Netea, Mihai G. ; Means, Terry K. ; Daly, Mark J. ; Xavier, Ramnik J. / Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation. In: Immunity. 2015 ; Vol. 43, No. 4. pp. 715-726.

@article{96895f3e5e36489284ac507afe1755fc,

title = "Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation",

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.",

keywords = "INHERITED CARD9 DEFICIENCY, COLITIS SUSCEPTIBILITY LOCI, INNATE IMMUNITY, BOWEL-DISEASE, ANTIVIRAL RESPONSE, DEEP DERMATOPHYTOSIS, FUNGAL-INFECTIONS, CANDIDA-ALBICANS, DENDRITIC CELLS, CROHNS-DISEASE",

author = "Zhifang Cao and Conway, {Kara L.} and Heath, {Robert J.} and Rush, {Jason S.} and Leshchiner, {Elizaveta S.} and Ramirez-Ortiz, {Zaida G.} and Nedelsky, {Natalia B.} and Hailiang Huang and Aylwin Ng and Agnes Gardet and Shih-Chin Cheng and Shamji, {Alykhan F.} and Rioux, {John D.} and Cisca Wijmenga and Netea, {Mihai G.} and Means, {Terry K.} and Daly, {Mark J.} and Xavier, {Ramnik J.}",

year = "2015",

month = oct,

day = "20",

doi = "10.1016/j.immuni.2015.10.005",

language = "English",

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Cao, Z, Conway, KL, Heath, RJ, Rush, JS, Leshchiner, ES, Ramirez-Ortiz, ZG, Nedelsky, NB, Huang, H, Ng, A, Gardet, A, Cheng, S-C, Shamji, AF, Rioux, JD, Wijmenga, C, Netea, MG, Means, TK, Daly, MJ & Xavier, RJ 2015, 'Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation', Immunity, vol. 43, no. 4, pp. 715-726. https://doi.org/10.1016/j.immuni.2015.10.005

Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-fungal Immunity and Intestinal Inflammation. / Cao, Zhifang; Conway, Kara L.; Heath, Robert J.; Rush, Jason S.; Leshchiner, Elizaveta S.; Ramirez-Ortiz, Zaida G.; Nedelsky, Natalia B.; Huang, Hailiang; Ng, Aylwin; Gardet, Agnes; Cheng, Shih-Chin; Shamji, Alykhan F.; Rioux, John D.; Wijmenga, Cisca; Netea, Mihai G.; Means, Terry K.; Daly, Mark J.; Xavier, Ramnik J.

In: Immunity, Vol. 43, No. 4, 20.10.2015, p. 715-726.

Research output: Contribution to journal › Article › Academic › peer-review

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AU - Cao, Zhifang

AU - Conway, Kara L.

AU - Heath, Robert J.

AU - Rush, Jason S.

AU - Leshchiner, Elizaveta S.

AU - Ramirez-Ortiz, Zaida G.

AU - Nedelsky, Natalia B.

AU - Huang, Hailiang

AU - Ng, Aylwin

AU - Gardet, Agnes

AU - Cheng, Shih-Chin

AU - Shamji, Alykhan F.

AU - Rioux, John D.

AU - Wijmenga, Cisca

AU - Netea, Mihai G.

AU - Means, Terry K.

AU - Daly, Mark J.

AU - Xavier, Ramnik J.

PY - 2015/10/20

Y1 - 2015/10/20

N2 - 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.

AB - 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.

KW - INHERITED CARD9 DEFICIENCY

KW - COLITIS SUSCEPTIBILITY LOCI

KW - INNATE IMMUNITY

KW - BOWEL-DISEASE

KW - ANTIVIRAL RESPONSE

KW - DEEP DERMATOPHYTOSIS

KW - FUNGAL-INFECTIONS

KW - CANDIDA-ALBICANS

KW - DENDRITIC CELLS

KW - CROHNS-DISEASE

U2 - 10.1016/j.immuni.2015.10.005

DO - 10.1016/j.immuni.2015.10.005

M3 - Article

C2 - 26488816

VL - 43

SP - 715

EP - 726

JO - Immunity

JF - Immunity

SN - 1074-7613

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ER -