Neddylation, an Emerging Mechanism Regulating Cardiac Development and Function.

Jie Li,Rodney Littlejohn,Huabo Su,Jinbao Liu,Jianqiu Zou

doi:10.3389/fphys.2020.612927

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.

Highlights

Heart failure is expected to remain the main cardiovascular event responsible for hospitalization throughout the world, including the US (Benjamin et al, 2019)
The proteasome and autophagy subsequently serve to degrade proteins that escape the surveillance of chaperones as well as those that are no longer needed by the cell
We first provide an overview of the neddylation pathway and outline the mechanisms by which neddylation modulates protein function; we focus on heart-specific functions of neddylation

Summary

Introduction

Heart failure is expected to remain the main cardiovascular event responsible for hospitalization throughout the world, including the US (Benjamin et al, 2019). Neddylation in the Heart distribution, activity and interactome of the modified substrates, and have pleiotropic impacts on the functionality of target proteins. Gene Ontology enrichment analyses revealed that these NEDD8 substrates belong to diverse protein categories, including DNA/RNA-binding proteins, chaperones, ribosomal proteins, chromatin architecture regulators, Ub- and UBL enzymes, and cytoskeletal proteins, indicating a likely crucial function for neddylation in these cellular processes.

Results

Conclusion