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Abnormal down‐regulation of PKC is responsible for giant granule formation in fibroblasts from CHS (beige) mice—a thiol proteinase inhibitor, E‐64‐d, prevents giant granule formation in beige fibroblasts
Author(s) -
Tanabe Fuminori,
Cui ShaoHui,
Ito Masahiko
Publication year - 2000
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.67.5.749
Subject(s) - granule (geology) , biology , microbiology and biotechnology , protein kinase c , signal transduction , paleontology
We have previously reported that the abnormally rapid down‐regulation of protein kinase C (PKC) activity is responsible for the cellular dysfunction in natural killer (NK) cells and polymorphonuclear leukocytes (PMNs) from Chediak‐Higashi syndrome (beige) mice. In this report, we examined whether the down‐regulation of PKC is associated with giant granule formation in fibroblasts from beige mice. In cultured beige fibroblasts, the membrane‐bound PKC activity declined significantly after phorbol ester stimulation. We found that E‐64‐d, which is a thiol proteinase inhibitor and protects PKC from calpain‐mediated proteolysis, reversed the declined PKC activity and prevented giant granule formation in beige fibroblasts. Moreover, E‐64‐d corrected the reduced lysosomal elastase and cathepsin G activity in beige fibroblasts. In contrast, specific PKC inhibitors, chelerythrin and calphostin C, promoted giant granule formation in normal fibroblasts. We also demonstrate that ceramide production is enhanced in beige fibroblasts and is involved in the rapid down‐regulation of PKC. These results suggest that the accelerated breakdown of PKC observed in beige fibroblasts is caused by enhanced ceramide production and is also responsible for giant granule formation. J. Leukoc. Biol. 67: 749–755; 2000.