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B Cell Development sans B Cell Receptor Responsiveness Due to Unfolded Protein Response-Triggered Mef2c Protein Degradation.
- Source :
-
Journal of Immunology . 11/15/2018, Vol. 201 Issue 10, p2885-2898. 14p. - Publication Year :
- 2018
-
Abstract
- BCR engagement leads to activation and clonal expansion of B cells. The I-A12% mutant mouse possesses a branch site point mutation in the H2-Aa gene that causes highly reduced I-Aa protein expression. As I-A is a heterodimer made up of I-Aa and I-Ab, reduced I-Aa results not only in reduced surface I-A expression but also in an excess of unpaired I-Ab. B cells that develop in I-A12% mice proliferated in response to LPS stimulation but failed to do so upon BCR stimulation. Developing I-A12% B cells were engaged in unfolded protein response due to an excess of unpaired I-Ab. BCR responsiveness was restored by transduced I-Aa expression and by BiP, the unfolded protein response sensor. Reducing the load of unpaired I-Ab also restored BCR responsiveness of I-A12% B cells. Mef2c protein, a transcription factor required for BCR-stimulated proliferation, was missing in I-A12% B cells, and that transduced Mef2c expression restored BCR responsiveness. Mef2c protein appeared in I-A12% B cells after addition of proteasome inhibitors. Mef2c degradation was mediated by Skp2 E3 ligase, and that knockdown of Skp2 mRNA in I-A12% B cells restored BCR responsiveness. Our results point to a generalized incompatibility between BCR responsiveness and increased Skp2 stability. They also imply the existence of regulatory mechanisms other than Ig gene rearrangement that govern Mef2c turnover in a specific, exquisite, and dynamic fashion. [ABSTRACT FROM AUTHOR]
- Subjects :
- *B cell receptors
*PROTEIN expression
*LYMPHOCYTES
*T cells
*PROTEOLYSIS
Subjects
Details
- Language :
- English
- ISSN :
- 00221767
- Volume :
- 201
- Issue :
- 10
- Database :
- Academic Search Index
- Journal :
- Journal of Immunology
- Publication Type :
- Academic Journal
- Accession number :
- 132884625
- Full Text :
- https://doi.org/10.4049/jimmunol.1800685