Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P11021 (
BiP
)
2,049
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:B Cell Development sans B Cell Receptor Responsiveness Due to Unfolded Protein Response-Triggered Mef2c Protein Degradation. 3030 29
