| First Author | Chen YT | Year | 2018 |
| Journal | J Immunol | Volume | 201 |
| Issue | 10 | Pages | 2885-2898 |
| PubMed ID | 30305329 | Mgi Jnum | J:267755 |
| Mgi Id | MGI:6258105 | Doi | 10.4049/jimmunol.1800685 |
| Citation | Chen YT, et al. (2018) B Cell Development sans B Cell Receptor Responsiveness Due to Unfolded Protein Response-Triggered Mef2c Protein Degradation. J Immunol 201(10):2885-2898 |
| abstractText | BCR engagement leads to activation and clonal expansion of B cells. The I-A(12%) 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-A(12%) mice proliferated in response to LPS stimulation but failed to do so upon BCR stimulation. Developing I-A(12%) 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-A(12%) B cells. Mef2c protein, a transcription factor required for BCR-stimulated proliferation, was missing in I-A(12%) B cells, and that transduced Mef2c expression restored BCR responsiveness. Mef2c protein appeared in I-A(12%) B cells after addition of proteasome inhibitors. Mef2c degradation was mediated by Skp2 E3 ligase, and that knockdown of Skp2 mRNA in I-A(12%) 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. |
