Insights into non-proteinaceous ubiquitination

Abstract

Ubiquitination plays a key role in the regulation of numerous diverse cellular functions. This process involves the covalent attachment of ubiquitin to protein substrates by a cascade of enzymes. In recent years, various non-proteinaceous substrates of ubiquitination have been discovered, expanding the potential for the functions of ubiquitination beyond its conventional role as a post-translational modification. Here, we profile the non-proteinaceous substrates of ubiquitination reported to date, the enzymes that regulate these activities, and the mechanistic details of substrate modification. The biological functions linked to these modifications are discussed, and finally, we highlight the challenges hindering further progress in the identification and functional characterization of non-proteinaceous substrates of ubiquitination within cellular contexts.

Keywords: adenosine diphosphate ribose; carbohydrate; lipid; nucleic acids; ubiquitin.

Figure 1. Types of non-proteinaceous substrates.

(A) Phospholipid, phosphatidylethanolamine, is conjugated to Ub by an amide bond which in yeast is catalyzed by Tul1 (left). The E3-like complex Atg12-Atg5 catalyzes the conjugation of Atg8 to phosphatidylethanolamine by an amide bond in yeast (right). (B) HOIL-1 catalyzes ubiquitination of glucosaccharides including unbranched glycogen and maltoheptaose (left). The linkage between Ub and the C6 hydroxyl of glucose is an oxyester bond. N-GlcNAc (right) is ubiquitinated on the C6 hydroxyl forming an oxyester bond. This is catalyzed by the SCF^FBS2-ARH1 complex. (C) Bacterial LPS is ubiquitinated by RNF213. The site of ubiquitination on Lipid A remains unknown. All chemical structures were produced using ChemSketch [7].]. HOIL-1, heme‐oxidized IRP2 ubiquitin ligase‐1; Tul1, transmembrane E3 ubiquitin-protein ligase 1; Ub, ubiquitin.

Figure 2. Nucleotides as non-proteinaceous substrates of Ub.

(A) ADPr is conjugated to Ub by an oxyester bond to the 3′ hydroxyl of the adenine proximal ribose ring. This reaction is catalyzed by all DELTEX family E3s and can occur on free ADPr (top), ADPr moieties on proteins (middle), and ADPr moieties on nucleic acids including DNA and RNA (bottom). (B) Only DTX3L and DTX3 from the DELTEX family E3s catalyze the ubiquitination of ssDNA and ssRNA. Ub is conjugated by an oxyester bond to the 3′ hydroxyl of the ribose ring of the 3′ end of the nucleotide. All chemical structures were produced using ChemSketch [7]. ADPr, adenosine diphosphate ribose; ssDNA, single-stranded RNA; ssRNA, single-stranded RNA; Ub, ubiquitin.