Emerging Roles and Research Tools of Atypical Ubiquitination

Abstract

Ubiquitination is a posttranslational modification characterized by the covalent attachment of ubiquitin molecules to protein substrates. The ubiquitination modification process is reversible, dynamic, and involved in the regulation of various biological processes, such as autophagy, inflammatory responses, and DNA damage responses. The forms of ubiquitin modification are very diverse, incorporating either a single ubiquitin molecule or a complicated ubiquitin polymer, and different types of ubiquitination usually elicit corresponding cellular responses. The development of research tools and strategies has afforded more detailed insight into atypical ubiquitin signaling pathways that were previously poorly understood. Here, an update on the understanding of atypical ubiquitin chain signaling pathways is provided and the recent development of representative research tools for ubiquitin systems is discussed. In addition, the future challenges in ubiquitin research are reflected on and summarized.

Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect

“…K11-linked polyubiquitin is known to control the cell cycle, proteasomal degradation, protein stability, mitophagy, trafficking, and endoplasmic reticulum-associated protein degradation [52][53][54]. K27-linked polyubiquitin activates kinases and regulates DNA repair [54]; K29-linked polyubiquitin plays a role in kinase modification and proteasomal/lysosomal degradation [55]; and K33-linked polyubiquitin induces kinases modification, innate immunity, and autophagy [54,56]. It is also known that K48-linked polyubiquitin induces proteasomal degradation [57], and the K63-linked polyubiquitin plays a role in protein kinase activation and DNA damage [58].…”

TRIMming Type I Interferon-Mediated Innate Immune Response in Antiviral and Antitumor Defense

“…Usually, a polyubiquitin chain contains more than 4 Ub molecules. In the last decade, non-canonical ubiquitination types on serine, threonine, and cysteine sites other than lysine site have been identified, and their importance in specific cellular functions has been recognized [ 23 , 24 ].…”

Targeting E3 Ubiquitin Ligases and Deubiquitinases in Ciliopathy and Cancer

“…Once ligated to its substrate, ubiquitin itself can be modified by ubiquitination of one or more of its seven lysine residues (K6, K11, K27, K29, K33, K48, and K63) or the N-terminal methionine [ 172 ]. Polyubiquitination can be homotypic (same linkage) or heterotypic (different linkage) [ 173 ] and it plays various roles in cell signaling regulation depending on the linkage type [ 173 ]. For example, homotypic K48 polyubiquitination is related to classical proteasomal degradation; homotypic K63 polyubiquitination regulates protein–protein interactions; homotypic K6 and K27 polyubiquitinations are involved in the DNA damage response; and homotypic K29 and K33 polyubiquitinations are linked to innate immunity.…”

“…β-arrestin is known to mediate the K63 polyubiquitination of SSTR3 and GPR161, but the identity of the E3 ubiquitin ligase(s) involved is unclear. One important task for the future is the development of novel tools that will enable the identification of all E3 ubiquitin ligase and DUB substrates, as well as their ubiquitination patterns, related to the assembly and disassembly of cilia [ 172 , 173 , 176 ].…”