Identification of a role for TRIM29 in the control of innate immunity in the respiratory tract.
The respiratory tract is heavily populated with innate immune cells, but the mechanisms that control such cells are poorly defined. Here we found that the E3 ubiquitin ligase TRIM29 was a selective regulator of the activation of alveolar macrophages, the expression of type I interferons and the production of proinflammatory cytokines in the lungs. We found that deletion of TRIM29 enhanced macrophage production of type I interferons and protected mice from infection with influenza virus, while challenge of Trim29-/-mice with Haemophilus influenzae resulted in lethal lung inflammation due to massive production of proinflammatory cytokines by macrophages. Mechanistically, we demonstrated that TRIM29 inhibited interferon-regulatory factors and signaling via the transcription factor NF-κB by degrading the adaptor NEMO and that TRIM29 directly bound NEMO and subsequently induced its ubiquitination and proteolytic degradation. These data identify TRIM29 as a key negative regulator of alveolar macrophages and might have important clinical implications for local immunity and immunopathology.
Immunobiology and Transplant Research Center, Houston Methodist Research Institute, Houston, Texas, USA.
Junji
J
Xing
Medimmune, Gaithersburg, Maryland, USA.
Leiyun
L
Weng
Immunobiology and Transplant Research Center, Houston Methodist Research Institute, Houston, Texas, USA.
Bin
B
Yuan
Immunobiology and Transplant Research Center, Houston Methodist Research Institute, Houston, Texas, USA.
Zhuo
Z
Wang
Immunobiology and Transplant Research Center, Houston Methodist Research Institute, Houston, Texas, USA.
Li
L
Jia
Immunobiology and Transplant Research Center, Houston Methodist Research Institute, Houston, Texas, USA.
Rui
R
Jin
Medimmune, Gaithersburg, Maryland, USA.
Hongbo
H
Lu
Immunobiology and Transplant Research Center, Houston Methodist Research Institute, Houston, Texas, USA.|Department of Surgery, Weill Cornell Medical College of Cornell University, New York, New York, USA.
Xian Chang
XC
Li
Medimmune, Gaithersburg, Maryland, USA.|Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China.
Yong-Jun
YJ
Liu
Immunobiology and Transplant Research Center, Houston Methodist Research Institute, Houston, Texas, USA.|Department of Surgery, Weill Cornell Medical College of Cornell University, New York, New York, USA.
Zhiqiang
Z
Zhang
D000818:Animals; D002478:Cells, Cultured; D006192:Haemophilus Infections / Q000276:immunology*; D006193:Haemophilus influenzae / Q000276:immunology*; D007113:Immunity, Innate; D009980:Influenza A virus / Q000276:immunology*; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D059748:Proteolysis; D012137:Respiratory System / Q000276:immunology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; C550082:TRIM29 protein, mouse; D014157:Transcription Factors
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