Molecular mechanisms of signaling via the docosanoid neuroprotectin D1 for cellular homeostasis and neuroprotection

Abstract

Docosahexaenoic acid, enriched in the brain and retina, generates docosanoids in response to disruptions of cellular homeostasis. Docosanoids include neuroprotectin D1 (NPD1), which is decreased in the CA1 hippocampal area of patients with early-stage Alzheimer's disease (AD). We summarize here how NPD1 elicits neuroprotection by up-regulating c-REL, a nuclear factor (NF)-κB subtype that, in turn, enhances expression of BIRC3 (baculoviral inhibitor of apoptosis repeat-containing protein 3) in the retina and in experimental stroke, leading to neuroprotection. Elucidating the mechanisms of action of docosanoids will contribute to managing diseases, including stroke, AD, age-related macular degeneration, traumatic brain injury, Parkinson's disease, and other neurodegenerations.

Keywords: NF-kB transcription factor; cell death; lipid signaling; neurodegenerative disease; retina.

Figure 1.

NPD1 inhibits apoptosis during UOS. Ligation of TNFR1 (highlighted in pink) stimulates the formation of complex I, which consists of TNFR1, TRADD, RIPK1, TNFR-associated factor 2 (TRAF2), BIRC2, and BIRC3. In the absence of BIRCs, RIP1 is deubiquitinated, which results in internalization of complex I, and procaspase-8 and RIP3 are integrated to form a new signaling complex (complex II or DISC). BIRCs suppress the formation of this complex, which acts as the activation platform for caspase-8, which induces cell death by the extrinsic pathway. Under conditions in which caspase activation is inhibited, RIP1 and RIP3 may be phosphorylated, thus forming a complex named necroptosome, which leads to cell death through a caspase-independent process known as necroptosis (highlighted in blue). UOS-triggered NPD1 exerts anti-apoptotic activity by increasing BIRC3 expression, resulting in subsequent augmentation of its anti-apoptotic effects. NPD1 also promotes dephosphorylation of Bcl-xL and promotes its heterodimerization with pro-apoptotic Bax, resulting in the consequent inactivation of this protein (highlighted in yellow). Z-VAD, benzyloxycarbonyl-VAD.

Figure 2.

Up-regulation of BIRC3 transcription by NPD1-dependent c-REL expression. Stimulus-driven proteosomal degradation of IκB proteins is mediated by the IKK complex, which liberates NF-κB dimers and results in their further translocation into the nucleus and transcriptional activity. NF-κB signaling often is divided into two types of pathways. The canonical pathway (yellow) is induced by most physiological NF-κB stimuli and is represented here by TNFR1 signaling in an IKKβ- and NEMO-dependent manner, with resulting activation of RelA containing heterodimers. In contrast, the non-canonical pathway (purple) is stimulated by certain TNF family cytokines, such as CD40L and lymphotoxin-β, and it involves IKKα-mediated phosphorylation and generation of p52-RELB complexes in a NIK-dependent manner, which is subject to a complex regulation by TRAF3, BIRC3, and other ubiquitin (UB) ligases. Activation of both pathways could generate c-REL containing hetero- or homodimers. NPD1, which is synthesized in response to oxidative stress in the eye and brain, triggers the production of c-REL-containing dimers independent of both the canonical and non-canonical NF-κB pathways, possibly by modifying the c-REL TBK1/IKKϵ axis via activation of a putative receptor (blue).

Figure 3.

Transcriptional regulation of c-REL by NPD1. The activation of either the canonical/non-canonical NF-κB pathways or c-REL carboxyl-terminal phosphorylation by TBK1/IKKϵ results in accumulation of REL proteins in the nucleus. Depending on the conditions, homo- or heterodimers containing c-REL can form. (1) c-REL promoter ligation eventuates in c-REL protein synthesis, which reinforces the autoregulation loop, (2) by increasing the content of c-REL in the NF-κB dimers, and (3) c-REL-containing dimers bind to the BIRC3 promoter to increase its expression activity, which ensures cell survival. NPD1 augments this auto-regulation loop by shifting the balance toward c-REL homodimers to intensify the expression of both BIRC3 and c-REL genes with subsequent protein synthesis. This shift allows for the restoration of cell homeostasis and thus promotes survival. The endoplasmic reticulum (ER) is depicted for ease of understanding the protein synthesis step in the pathway.