Cytosolic Pellino-1-Mediated K63-Linked Ubiquitination of IRF5 in M1 Macrophages Regulates Glucose Intolerance in Obesity

• Published in: Cell reports (Cambridge) Vol. 20; no. 4; pp. 832 - 845
• Main Authors: Kim, Donghyun, Lee, Ho, Koh, Jaemoon, Ko, Jae Sung, Yoon, Bo Ruem, Jeon, Yoon Kyung, Cho, Young Min, Kim, Tae Han, Suh, Yun-Suhk, Lee, Hyuk-Joon, Yang, Han-Kwang, Park, Kyong Soo, Kim, Hye Young, Lee, Chang Woo, Lee, Won-Woo, Chung, Doo Hyun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.07.2017; Elsevier
• Subjects: Animals; Chromatin Immunoprecipitation; cytosolic mediator; Female; Flow Cytometry; Glucose Intolerance - genetics; Glucose Intolerance - metabolism; glucose metabolism; Humans; Immunoblotting; Immunoprecipitation; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; IRF5; M1 polarization; macrophages; Macrophages - metabolism; Male; Mice; Mice, Knockout; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; obesity; Obesity - genetics; Obesity - metabolism; Pellino-1; Signal Transduction - genetics; Signal Transduction - physiology; ubiquitin E3 ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; ubiquitination; Ubiquitination - genetics; Ubiquitination - physiology; macrophages; ubiquitination; ubiquitin E3 ligase; Pellino-1; IRF5; M1 polarization; glucose metabolism; cytosolic mediator; obesity
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.06.088

IRF5 is a signature transcription factor that induces M1 macrophage polarization. However, little is known regarding cytosolic proteins that induce IRF5 activation for M1 polarization. Here, we report the interaction between ubiquitin E3 ligase Pellino-1 and IRF5 in the cytoplasm, which increased nuclear translocation of IRF5 by K63-linked ubiquitination in human and mouse M1 macrophages. LPS and/or IFN-γ increased Pellino-1 expression, and M1 polarization was attenuated in Pellino-1-deficient macrophages in vitro and in vivo. Defective M1 polarization in Pellino-1-deficient macrophages improved glucose intolerance in mice fed a high-fat diet. Furthermore, macrophages in adipose tissues from obese humans exhibited increased Pellino-1 expression and IRF5 nuclear translocation compared with nonobese subjects, and these changes are associated with insulin resistance index. This study demonstrates that cytosolic Pellino-1-mediated K63-linked ubiquitination of IRF5 in M1 macrophages regulates glucose intolerance in obesity, suggesting a cytosolic mediator function of Pellino-1 in TLR4/IFN-γ receptor-IRF5 axis during M1 polarization. [Display omitted] •Pellino-1 promotes macrophage M1 polarization•Pellino-1 induces K63-dependent ubiquitination and nuclear translocation of IRF5•Pellino-1 knockout mice show reduction of obesity and glucose intolerance•Pellino-1 expression correlates with HOMA-IR and M1 macrophage in human Kim et al. demonstrate that ubiquitin E3 ligase Pellino-1 promotes macrophage M1 polarization and obesity-induced glucose intolerance in mice and humans. Furthermore, Pellino-1 induces nuclear translocation of IRF5 by binding and K63-linked ubiquitination.