Neddylation steers the fate of cellular receptors

Abstract

Cellular receptors regulate physiological responses by interacting with ligands, thus playing a crucial role in intercellular communication. Receptors are categorized on the basis of their location and engage in diverse biochemical mechanisms, which include posttranslational modifications (PTMs). Considering the broad impact and diversity of PTMs on cellular functions, we focus narrowly on neddylation, a modification closely resembling ubiquitination. We systematically organize its canonical and noncanonical roles in modulating proteins associated with cellular receptors with the goal of providing a more detailed perspective on the intricacies of both intracellular and cell-surface receptors.

Fig. 1. The process and roles of neddylation.

Neddylation is a sequential process in which N8 is activated by the E1 enzyme, loaded onto the E2 enzyme, and conjugated to the substrate by the E3 enzyme. E1 enzyme activity can be blocked by neddylation inhibitors and E1 can be recycled through N8 isopeptidase. Neddylation can be divided into two regulated pathways, the canonical regulated pathway and the noncanonical regulated pathway, depending on how the substrates are involved. In the canonical regulated neddylation pathway, N8 conjugation to the cullin protein (a subunit of cullin-RING ubiquitin ligase) activates the CRL, leading to protein ubiquitination. The noncanonical regulated neddylation pathway occurs when N8 conjugates with substrates other than cullin proteins. Unlike the canonical neddylation pathway, noncullin-regulated neddylated proteins trigger a diverse range of effects on substrate proteins, inducing changes in their stability, function, and subcellular localization.

Fig. 2. Neddylation plays diverse roles in various types of cellular receptors.

Receptors are categorized into membrane and intracellular receptors based on their location. Membrane receptors include ion channel-linked, G-protein-coupled, and enzyme-linked receptors, which transmit signals from outside the cell, triggering diverse cellular responses. Intracellular receptors are divided into Type I (cytoplasmic) and Type II (nuclear) receptors, which are primarily activated by hydrophobic molecules such as hormones. They act as transcription factors, regulating various cellular responses. Neddylation has diverse effects on receptor functionality, ultimately altering cellular physiology in response to external stimuli. In some cases, neddylation enhances cellular signaling by increasing receptor stability, while in others it triggers ubiquitin–proteasomal degradation leading to reduced receptor levels and attenuated signaling. Neddylation can also enhance signal transduction by promoting receptor endocytosis. Furthermore, it diminishes the transcriptional activity of intracellular receptors by disrupting receptor‒ligand binding interactions.

Fig. 3. Receptor neddylation plays diverse roles in physiological and pathological processes.

The response to receptor neddylation varies across different tissues and diseases. This diagram summarizes the effects of receptor neddylation investigated across various physiological responses, illustrating whether altering receptor function through neddylation inhibition has beneficial (positive) effects (highlighted in red) or harmful (negative) effects (highlighted in blue) on the respective tissues and diseases.