Protein kinase cα and ζ differentially regulate death-inducing signaling complex formation in cigarette smoke extract-induced apoptosis

Jeong Woong Park, Hong Pyo Kim, Seon Jin Lee, Xue Wang, Yong Wang, Emeka Ifedigbo, Simon C. Watkins, Motoi Ohba, Stefan W. Ryter, Yatin M. Vyas, Augustine M.K. Choi

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43 Citations (SciVal)


Cigarette smoke, a major risk factor in emphysema, causes cell death by incompletely understood mechanisms. Death-inducing signaling complex (DISC) formation is an initial event in Fas-mediated apoptosis. We demonstrate that cigarette smoke extract (CSE) induces DISC formation in human lung fibroblasts (MRC-5) and promotes DISC trafficking from the Golgi complex to membrane lipid rafts. We demonstrate a novel role of protein kinase C (PKC) in the regulation of DISC formation and trafficking. The PKC isoforms, PKCα,ζ ε, and η, were activated by CSE exposure. Overexpression of wild-type PKCα inhibited, while PKCζ promoted, CSE-induced cell death. Dominant-negative (dn)PKCζ protected against CSE-induced cell death by suppressing DISC formation and caspase-3 activation, while dnPKCα enhanced cell death by promoting these events. DISC formation was augmented by wortmannin, an inhibitor of PI3K. CSE-induced Akt phosphorylation was reduced by dnPKCα, but it was increased by dnPKCζ. Expression of PKCα in vivo inhibited DISC formation, caspase-3/8 activation, lung injury, and cell death after prolonged cigarette smoke exposure, whereas expression of PKCζ promoted caspase-3 activation. In conclusion, CSE-induced DISC formation is differentially regulated by PKCα and PKCζ via the PI3K/Akt pathway. These results suggest that modulation of PKC may have therapeutic potential in the prevention of smoke-related lung injury.

Original languageEnglish (US)
Pages (from-to)4668-4678
Number of pages11
JournalJournal of Immunology
Issue number7
StatePublished - Apr 1 2008

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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