Schematic of protein kinase Cδ (PKCδ) activation by proteolytic cleavage downstream of tumor necrosis factor (TNF) signaling in dopaminergic neurons.
(1) Sustained TNF signaling leads to caspase-8 activation, presumably by autoproteolytic cleavage at the receptor complex (2). Active caspase-8 leads to downstream activation of caspase-3, which can be blocked by the caspase-8 inhibitor IETD-fmk (3). Caspase-3 activates PKCδ by proteolytic cleavage (4) at the hinge region (shown in red), releasing the catalytic fragment and causing constitutive activation of the kinase (5). The constitutively active PKCδ catalytic fragment mediates proapoptotic signaling by phosphorylation of its downstream substrates, resulting in DNA fragmentation and dopaminergic cell death (6). Blocking the PKCδ signaling pathway using siRNA, targeted gene knockout or a caspase-3 cleavage-resistant mutant can protect against dopaminergic cell death induced by TNF toxicity.