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B Protein Degradation Mediate CD40 Ligand Rescue of WEHI 231 Immature B Cells from Receptor-Mediated Apoptosis1
Departments of
*
Microbiology and
Biochemistry, Boston University Medical School, Boston, MA 02118
Recently, we demonstrated maintenance of nuclear factor
(NF)-
B/Rel factors plays a major role in B cell survival. Treatment
of WEHI 231 immature B cells with an Ab against the surface IgM protein
(anti-IgM) induces apoptosis that can be rescued by engagement of
CD40 receptor. The dramatic decrease in high basal levels of
NF-B/Rel activity induced by anti-IgM treatment led to cell
death. CD40 ligand (CD40L) treatment prevented the drop in NF-B/Rel
factor binding by inducing a sustained decrease in inhibitor (I)
B-
and transient decrease in IB-ß protein levels. In this
study, we have investigated the regulation of these
NF-B/Rel-inhibitory proteins. In exponentially growing WEHI 231
cells, the IB- and IB-ß proteins decayed with an approximate
t1/2 of 38 and 76 min, respectively,
which was blocked effectively upon addition of the proteasome-specific
inhibitor (benzylcarbonyl)-Leu-Leu-phenylalaninal (Z-LLF-CHO). Anti-IgM
treatment stabilized IB- and IB-ß proteins. CD40L treatment
resulted in a dramatic decrease in t1/2 (<5
min) for both IB molecules, which was inhibited by addition of
Z-LLF-CHO. CD40L treatment also caused a delayed increase in IB-ß
mRNA levels, most likely contributing to the observed recovery of
IB-ß levels. Microinjection of IB--glutathione
S-transferase fusion protein into nuclei of WEHI 231 cells
ablated protection by CD40L from receptor-mediated killing.
Furthermore, CD40L rescued apoptosis induced upon microinjection of a
vector expressing wild-type IB-, but not a 32A/36A mutant form of
IB-, unable to be phosphorylated and hence degraded. Thus,
control of turnover of IB proteins by CD40L plays a major role in
maintenance of NF-B/Rel and resultant rescue of WEHI 231 cells from
apoptosis.
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