MCP-induced protein 1 deubiquitinates TRAF proteins and negatively regulates JNK and NF-kappaB signaling.
The intensity and duration of macrophage-mediated inflammatory responses are controlled by proteins that modulate inflammatory signaling pathways. MCPIP1 (monocyte chemotactic protein-induced protein 1), a recently identified CCCH Zn finger-containing protein, plays an essential role in controlling macrophage-mediated inflammatory responses. However, its mechanism of action is poorly understood. In this study, we show that MCPIP1 negatively regulates c-Jun N-terminal kinase (JNK) and NF-κB activity by removing ubiquitin moieties from proteins, including TRAF2, TRAF3, and TRAF6. MCPIP1-deficient mice spontaneously developed fatal inflammatory syndrome. Macrophages and splenocytes from MCPIP1(-/-) mice showed elevated expression of inflammatory gene expression, increased JNK and IκB kinase activation, and increased polyubiquitination of TNF receptor-associated factors. In vitro assays directly demonstrated the deubiquitinating activity of purified MCPIP1. Sequence analysis together with serial mutagenesis defined a deubiquitinating enzyme domain and a ubiquitin association domain in MCPIP1. Our results indicate that MCPIP1 is a critical modulator of inflammatory signaling.
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
Jian
J
Liang
Yasser
Y
Saad
Tianhua
T
Lei
Jing
J
Wang
Dongfei
D
Qi
Qinglin
Q
Yang
Pappachan E
PE
Kolattukudy
Mingui
M
Fu
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D053583:Interleukin-1beta / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D012260:Ribonucleases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination
D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D025801:Ubiquitin; D048031:JNK Mitogen-Activated Protein Kinases; D012260:Ribonucleases; C541320:Zc3h12a protein, mouse