Proteolytic Activation of Protein Kinase C δ by an ICE/CED 3-like Protease Induces Characteristics of Apoptosis

TLDR

PKCδ is proteolytically activated at the onset of apoptosis triggered by DNA damage, TNF, and anti‑Fas, yet its contribution to apoptosis induction is not yet understood. Cleavage of PKCδ at DMQD330N by the cysteine protease CPP32 generates an active fragment that, when overexpressed, induces chromatin condensation, nuclear fragmentation, sub‑G1 DNA, and cell death, whereas full‑length or inactive PKCδ does not, demonstrating that CPP32‑mediated PKCδ activation drives apoptotic phenotypes.

Abstract

Recent studies have shown that protein kinase C (PKC) δ is proteolytically activated at the onset of apoptosis induced by DNA-damaging agents, tumor necrosis factor, and anti-Fas antibody. However, the relationship of PKCδ cleavage to induction of apoptosis is unknown. The present studies demonstrate that full-length PKCδ is cleaved at DMQD330N to a catalytically active fragment by the cysteine protease CPP32. The results also demonstrate that overexpression of the catalytic kinase fragment in cells is associated with chromatin condensation, nuclear fragmentation, induction of sub-G1 phase DNA and lethality. By contrast, overexpression of full-length PKCδ or a kinase inactive PKCδ fragment had no detectable effect. The findings suggest that proteolytic activation of PKCδ by a CPP32-like protease contributes to phenotypic changes associated with apoptosis.