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Divisions of Cytokine Biology and Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD 20852
IL-12 is a heterodimeric cytokine produced by APC that critically
regulates cell-mediated immunity. Because of its crucial function
during immune responses, IL-12 production is stringently regulated, in
part through transcriptional control of its p35 subunit, which requires
the differentiative effects of IFN-
for expression. To determine
whether post-transcriptional aspects of IL-12 production might be
regulated, we examined intracellular protein processing of each
subunit. We report here that p40 and p35 subunits are processed by
disparate pathways. Whereas processing of p40 conforms to the
cotranslational model of signal peptide removal concomitant with
translocation into the endoplasmic reticulum (ER), processing of p35
does not. Translocation of the p35 preprotein into the ER was not
accompanied by cleavage of the signal peptide; rather, removal of the
p35 signal peptide occurred via two sequential cleavages. The first
cleavage took place within the ER, and the cleavage site localized to
the middle of the hydrophobic region of the signal peptide. Although
the preprotein was glycosylated upon entry into the ER, its
glycosylation status did not affect primary cleavage. Subsequently, the
remaining portion of the p35 signal peptide was removed by a second
cleavage, possibly involving a metalloprotease, concomitant with
additional glycosylation and secretion. Secretion could be inhibited by
mutation of the second cleavage site or by inhibition of glycosylation
with tunicamycin. In contrast, p40 secretion was not affected by
inhibition of glycosylation. Our findings demonstrate that IL-12
subunits are processed by disparate pathways and suggest new modalities
for regulation of IL-12 production.
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