S. Macintyre et al., 2 CARBOXYLESTERASES BIND C-REACTIVE PROTEIN WITHIN THE ENDOPLASMIC-RETICULUM AND REGULATE ITS SECRETION DURING THE ACUTE-PHASE RESPONSE, The Journal of biological chemistry, 269(39), 1994, pp. 24496-24503
We have previously reported that C-reactive protein (CRP) is normally
synthesized by rabbit hepatocytes at relatively low rates and is retai
ned in the endoplasmic reticulum (ER), apparently by specific interact
ion with a 60-kDa lumenal ER protein. During the acute phase response
to tissue injury, a marked increase in CRP synthesis is associated wit
h a decrease in the CRP binding capacity of the 60-kDa protein, with a
ccompanying rapid secretion of CRP. In the present studies, we purifie
d two 60-kDa ER lumenal glycoproteins (referred to as gp60a and gp60b)
capable of binding CRP. gp60b, though present at only 5% the level of
gp60a, was found to account for 80% of the total CRP binding capacity
. Amino-terminal amino acid sequence analysis and biochemical characte
rization identified gp60a and gp60b as two microsomal carboxylesterase
s previously reported by others to contain COOH-terminal ER retention
signals (HIEL and HTEL). The CRP binding activities of gp60a and gp60b
were found to be independent of their esterase activities. In animals
undergoing the acute phase response, the levels of gp60a and gp60b we
re diminished by about 50%, but the CRP binding capacities were reduce
d by 4-6-fold for gp60a and 25-30-fold for gp60b. These findings indic
ate that CRP is normally retained within the ER via interaction with g
p60a and gp60b, while during the acute phase response a decrease in th
e CRP binding affinity of these proteins, particularly gp60b, results
in efficient secretion of CRP.