A p38 MAPK-MEF2C pathway regulates B-cell proliferation

[Guest guest]

A p38 MAPK-MEF2C pathway regulates B-cell proliferation

1.. Khiema,

2.. G. Cysterb,

3.. J. Schwarzc, and

4.. L. Blacka,1

Author Affiliations

1.. aCardiovascular Research Institute and Department of Biochemistry and

Biophysics, University of California, San Francisco, CA 94158-2517;

2.. bDepartment of Microbiology and Immunology, University of California, San

Francisco CA 94143-0414; and

3.. cCenter for Cardiovascular Sciences, Albany Medical College, Albany, NY

12208

1.. Edited by N. Olson, University of Texas Southwestern Medical Center,

Dallas, TX, and approved September 12, 2008 (received for review May 19, 2008)

Abstract

B lymphocytes are an integral part of the adaptive immune system. On antigen

binding to the B-cell receptor (BCR), B cells rapidly proliferate and

differentiate into antibody-secreting plasma cells. The p38 mitogen-activated

protein kinase (MAPK) pathway functions downstream of the BCR to control cell

proliferation, but the transcriptional effectors of this pathway in B cells have

remained elusive. In the present study, we inactivated Mef2c exclusively in B

cells by conditional gene targeting in mice. Loss of MEF2C function resulted in

a reduced immune response to antigen, defective germinal center formation, and a

severe defect in B-cell proliferation, and we show that MEF2C regulates

proliferation in response to BCR stimulation via the p38 MAPK pathway. p38

directly phosphorylates MEF2C via three residues in the C-terminal

transactivation domain, establishing MEF2C as a direct transcriptional effector

of BCR signaling via p38 MAPK.