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Review
. 2020 Dec 17:11:612927.
doi: 10.3389/fphys.2020.612927. eCollection 2020.

Neddylation, an Emerging Mechanism Regulating Cardiac Development and Function

Jie Li  1 , Jianqiu Zou  1 , Rodney Littlejohn  1 , Jinbao Liu  2 , Huabo Su  1
Affiliations
Review

Neddylation, an Emerging Mechanism Regulating Cardiac Development and Function

Jie Li et al. Front Physiol. .

Abstract

Defects in protein quality control have been increasingly recognized as pathogenic factors in the development of heart failure, a persistent devastating disease lacking efficacious therapies. Ubiquitin and ubiquitin-like proteins, a family of post-translational modifying polypeptides, play important roles in controlling protein quality by maintaining the stability and functional diversity of the proteome. NEDD8 (neural precursor cell expressed, developmentally downregulated 8), a small ubiquitin-like protein, was discovered two decades ago but until recently the biological significance of NEDD8 modifications (neddylation) in the heart has not been appreciated. In this review, we summarize the current knowledge of the biology of neddylation, highlighting several mechanisms by which neddylation regulates the function of its downstream targets, and discuss the expanding roles for neddylation in cardiac physiology and disease, with an emphasis on cardiac protein quality control. Finally, we outline challenges linked to the study of neddylation in health and disease.

Keywords: Heart Failure; NEDD8 (neural precursor cell expressed developmentally down-regulated 8); Neddylation; Ubiquitin-like protein; cardiomyopathy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Neddylation has emerged as a powerful mechanism for regulating cellular physiology in a variety of tissues. Dysregulation of neddylation has been linked to vascular diseases, such as neointima formation and atherosclerosis, liver steatosis, cognitive deficits, tumor growth, obesity, and heart failure. Modulation of this pathway may provide opportunities for combating diverse human disorders.
FIGURE 2
FIGURE 2
The neddylation cascade. NEDD8 is first synthesized as a precursor that is proteolytically processed to expose its C-terminal glycine. The matured NEDD8 is then activated by forming a thioester linkage with NAE—a heterodimer of UBA3 and NAE1—in an ATP-dependent manner. Activated NEDD8 is then transferred from the active cysteine site of NAE to the active cysteine site of E2 UBE2M or UBE2F. Interaction of E2 with an E3 ligase positions the C-terminal glycine for nucleophilic attack by the lysine residue on the substrate, resulting in covalent linkage of NEDD8 to target proteins via an isopeptide bond. Protein substrates can be modified by mono-, multi-mono, or a chain of NEDD8 via different linkages. The deneddylases, NEDP1 and CSN, catalyze the removal of NEDD8 moieties from substrates. MLN4924 is a specific neddylation inhibitor that acts by preventing NAE-mediated NEDD8 activation.
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