Paul W Bates | PubMed Health

PubMed2004

Expanded nuclear roles for IkappaBs.

I kappa B (IkappaB) was initially identified as a factor that inhibits DNA binding and nuclear translocation of the transcription factor nuclear factor kappa B (NF-kappaB). Recently, however, IkappaB family members have demonstrated direct nuclear roles in regulating NF-kappaB-dependent transcription. Some IkappaB proteins, including IkappaBalpha and IkappaBbeta, can regulate transcription by modulating the concentration of active NF-kappaB complexes within the nucleus. Others, such as IkappaBzeta and Bcl-3, can directly activate transcription by forming transcriptional complexes at gene promoters. Thus, IkappaB proteins play important nuclear roles in regulating NF-kappaB-dependent transcription after stimulation with various extracellular signals.

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PubMed2002

Endoplasmic reticulum localization of the low density lipoprotein receptor mediates presecretory degradation of apolipoprotein B.

Mutations in the low density lipoprotein (LDL) receptor (LDLR) cause hypercholesterolemia because of inefficient LDL clearance from the circulation. In addition, there is a paradoxical oversecretion of the metabolic precursor of LDL, very low density lipoprotein (VLDL). We recently demonstrated that the LDLR mediates pre-secretory degradation of the major VLDL protein, apolipoprotein B (apoB). Kinetic studies suggested that the degradation process is initiated in the secretory pathway. Here, we evaluated the ability of several LDLR variants that are stalled within the secretory pathway to regulate apoB secretion. Both a naturally occurring mutant LDLR and an LDLR consisting of only the ligand-binding domains and a C-terminal endoplasmic reticulum (ER) retention sequence were localized to the ER and not at the cell surface. In the presence of either of the ER-localized LDLRs, apoB secretion was essentially abolished. When the ligand-binding domain of the truncated receptor was mutated the receptor was unable to block apoB secretion, indicating that the inhibition of apoB secretion depends on the ability of the LDLR to bind to its ligand. These findings establish LDLR-mediated pre-secretory apoB degradation as a pathway distinct from reuptake of nascent lipoproteins at the cell surface. The LDLR provides an example of a receptor that modulates export of its ligand from the ER.

Animals↗