The E3 ubiquitin ligase Mule acts through the ATM-p53 axis to maintain B lymphocyte homeostasis.
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.
The Campbell Family Institute for Cancer Research and 2 Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2M9, Canada. zhenyuehao@gmail.com
Zhenyue
Z
Hao
Gordon S
GS
Duncan
Yu-Wen
YW
Su
Wanda Y
WY
Li
Jennifer
J
Silvester
Claire
C
Hong
Han
H
You
Dirk
D
Brenner
Chiara
C
Gorrini
Jillian
J
Haight
Andrew
A
Wakeham
Annick
A
You-Ten
Susan
S
McCracken
Andrew
A
Elia
Qinxi
Q
Li
Jacqui
J
Detmar
Andrea
A
Jurisicova
Elias
E
Hobeika
Michael
M
Reth
Yi
Y
Sheng
Philipp A
PA
Lang
Pamela S
PS
Ohashi
Qing
Q
Zhong
Xiaodong
X
Wang
Tak W
TW
Mak
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D004249:DNA Damage / Q000276:immunology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D023061:Gene Order; D018390:Gene Targeting; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D056724:Immunity, Humoral / Q000235:genetics; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007132:Immunoglobulin Isotypes / Q000097:blood; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007132:Immunoglobulin Isotypes; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C502831:Huwe1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases