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The zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim
Jurado, Sabine Gleeson, Kimberly O’Donnell, Kristy Izon, David J. Walkley, Carl R. Strasser, Andreas Tarlinton, David M. Heierhorst, Jörg
Jurado, Sabine
Gleeson, Kimberly
O’Donnell, Kristy
Izon, David J.
Walkley, Carl R.
Strasser, Andreas
Tarlinton, David M.
Heierhorst, Jörg
Abstract
Developing B lymphocytes expressing defective or autoreactive pre-B or B cell receptors (BCRs) are eliminated by programmed cell death, but how the balance between death and survival signals is regulated to prevent immunodeficiency and autoimmunity remains incompletely understood. In this study, we show that absence of the essential ATM (ataxia telangiectasia mutated) substrate Chk2-interacting Zn2+-finger protein (ASCIZ; also known as ATMIN/ZNF822), a protein with dual functions in the DNA damage response and as a transcription factor, leads to progressive cell loss from the pre-B stage onwards and severely diminished splenic B cell numbers in mice. This lymphopenia cannot be suppressed by deletion of p53 or complementation with a prearranged BCR, indicating that it is not caused by impaired DNA damage responses or defective V(D)J recombination. Instead, ASCIZ-deficient B cell precursors contain highly reduced levels of DYNLL1 (dynein light chain 1; LC8), a recently identified transcriptional target of ASCIZ, and normal B cell development can be restored by ectopic Dynll1 expression. Remarkably, the B cell lymphopenia in the absence of ASCIZ can also be fully suppressed by deletion of the proapoptotic DYNLL1 target Bim. Our findings demonstrate a key role for ASCIZ in regulating the survival of developing B cells by activating DYNLL1 expression, which may then modulate Bim-dependent apoptosis.
Keywords
Date
2012
Type
Journal article
Journal
Journal of Experimental Medicine
Book
Volume
209
Issue
9
Page Range
1629-1639
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
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Open Access Status
License
All rights reserved
File Access
Controlled