Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling

Masahiro Yamamoto¹, Toru Okamoto², Kiyoshi Takeda³, Shintaro Sato⁴, Hideki Sanjo¹, Satoshi Uematsu¹, Tatsuya Saitoh^1, 5, Naoki Yamamoto⁵, Hiroaki Sakurai⁶, Ken J Ishii⁴, Shoji Yamaoka⁵, Taro Kawai⁴, Yoshiharu Matsuura², Osamu Takeuchi^1, 4 & Shizuo Akira^1, 4

¹  Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.

²  Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.

³  Department of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.

⁴  ERATO, Japan Science and Technology Corporation, Osaka 565-0871, Japan.

⁵  Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.

⁶  Division of Pathogenic Biochemistry, Institute of Natural Medicine, 21st Century Center of Excellence Program, Toyama Medical and Pharmaceutical University, Toyama 930-0194, Japan.

The Ubc13 E2 ubiquitin-conjugating enzyme is key in the process of 'tagging' target proteins with lysine 63–linked polyubiquitin chains, which are essential for the transmission of immune receptor signals culminating in activation of the transcription factor NF-B. Here we demonstrate that conditional ablation of Ubc13 resulted in defective B cell development and in impaired B cell and macrophage activation. In response to all tested stimuli except tumor necrosis factor, Ubc13-deficient cells showed almost normal NF-B activation but considerably impaired activation of mitogen-activated protein kinase. Ubc13-induced activation of mitogen-activated protein kinase required, at least in part, ubiquitination of the adaptor protein IKK. These results show that Ubc13 is key in the mammalian immune response.

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