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

• Main Authors: Donghyun Kim, Ho Lee, Jaemoon Koh, Jae Sung Ko, Bo Ruem Yoon, Yoon Kyung Jeon, Young Min Cho, Tae Han Kim, Yun-Suhk Suh, Hyuk-Joon Lee, Han-Kwang Yang, Kyong Soo Park, Hye Young Kim, Chang Woo Lee, Won-Woo Lee, Doo Hyun Chung
• Format: Article
• Language: English
• Published: Elsevier 2017-07-01
• Series: Cell Reports
• Subjects: Pellino-1; ubiquitin E3 ligase; IRF5; ubiquitination; macrophages; M1 polarization; cytosolic mediator; glucose metabolism; obesity
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124717309361

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.