The E3 ubiquitin ligase Mule acts through the ATM-p53 axis to maintain B lymphocyte homeostasis

• Published in: The Journal of experimental medicine 2012-01, Vol.209 (1), p.173-186
• Main Authors: Hao, Zhenyue, Duncan, Gordon S, Su, Yu-Wen, Li, Wanda Y, Silvester, Jennifer, Hong, Claire, You, Han, Brenner, Dirk, Gorrini, Chiara, Haight, Jillian, Wakeham, Andrew, You-Ten, Annick, McCracken, Susan, Elia, Andrew, Li, Qinxi, Detmar, Jacqui, Jurisicova, Andrea, Hobeika, Elias, Reth, Michael, Sheng, Yi, Lang, Philipp A, Ohashi, Pamela S, Zhong, Qing, Wang, Xiaodong, Mak, Tak W
• Format: Article
• Language: English
• Subjects: Animals; Ataxia Telangiectasia Mutated Proteins; B-Lymphocytes - cytology; B-Lymphocytes - enzymology; B-Lymphocytes - immunology; Cell Cycle Proteins - metabolism; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Line; Cell Proliferation; DNA Damage - immunology; DNA-Binding Proteins - metabolism; Female; Gene Order; Gene Targeting; Homeostasis - genetics; Homeostasis - immunology; Immunity, Humoral - genetics; Immunoglobulin Class Switching - genetics; Immunoglobulin Isotypes - blood; Lymphocyte Activation - genetics; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein-Serine-Threonine Kinases - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - metabolism; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20111363

Cellular homeostasis is controlled by pathways that balance cell death with survival. Mcl-1 ubiquitin ligase E3 (Mule) is an E3 ubiquitin ligase that targets the proapoptotic molecule p53 for polyubiquitination and degradation. To elucidate the role of Mule in B lymphocyte homeostasis, B cell-specific Mule knockout (BMKO) mice were generated using the Cre-LoxP recombination system. Analysis of BMKO mice showed that Mule was essential for B cell development, proliferation, homeostasis, and humoral immune responses. p53 transactivation was increased by two- to fourfold in Mule-deficient B cells at steady state. Genetic ablation of p53 in BMKO mice restored B cell development, proliferation, and homeostasis. p53 protein was increased in resting Mule-deficient mouse embryonic fibroblasts (MEFs) and embryonic stem (ES) cells. Loss of Mule in both MEFs and B cells at steady state resulted in increased levels of phospho-ataxia telangiectasia mutated (ATM) and the ATM substrate p53. Under genotoxic stress, BMKO B cells were resistant to apoptosis, and control MEFs exhibited evidence of a physical interaction between Mule and phospho-ATM. Phospho-ATM, phospho-p53, and Brca1 levels were reduced in Mule-deficient B cells and MEFs subjected to genotoxic stress. Thus, Mule regulates the ATM-p53 axis to maintain B cell homeostasis under both steady-state and stress conditions.