The E3 ubiquitin ligase mule acts through the ATM-p53 axis to maintain b lymphocyte homeostasis

Zhenyue Hao*, Gordon S. Duncan, Yu Wen Su, Wanda Y. Li, Jennifer Silvester, Claire Hong, Han You, Dirk Brenner, Chiara Gorrini, Jillian Haight, Andrew Wakeham, Annick You-Ten, Susan McCracken, Andrew Elia, Qinxi Li, Jacqui Detmar, Andrea Jurisicova, Elias Hobeika, Michael Reth, Yi ShengPhilipp A. Lang, Pamela S. Ohashi, Qing Zhong, Xiaodong Wang, Tak W. Mak

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

53 Citations (Scopus)


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 Muledeficient 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.

Original languageEnglish
Pages (from-to)173-186
Number of pages14
JournalJournal of Experimental Medicine
Issue number1
Publication statusPublished - Jan 2012
Externally publishedYes


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