This chapter recapitulates our current knowledge about the functions of the interferon stimulated gene 15 (ISG15) system in vivo with a specific focus on physiological aspects and the biological relevance of ISG15 conjugation and deconjugation. ISG15 contains two domains with structural...

Cdc48 (alias p97, VCP) is an important motor and regulator for the turnover of ubiquitylated proteins, both in proteasomal degradation and in nonproteolytic pathways. The diverse cellular tasks of Cdc48 are controlled by a large number of cofactors. Substrate‑recruiting cofactors mediate the...

It is commonly assumed that the p53 tumor suppressor pathway is deregulated in most if not all human cancers. Thus, the past two decades have witnessed intense efforts to identify and characterize the growth‑suppressive properties of p53 as well as the proteins and mechanisms involved in...

The ubiquitin conjugation system regulates a wide variety of biological phenomena, in most cases, by modulating protein function via polyubiquitin conjugation. Several types of polyubiquitin chains exist in cells and the type of chain conjugated to a protein seems to determine how the protein...

This chapter reviews the current literature to highlight the biological mechanisms mediated via the enzymatic actions of the SUMO‑specific protease family. All members of this cysteine protease family express isopeptidase activity to deSUMOylate conjugated cellular protein targets. Here, we...

Transcription factor NF‑κB regulates the physiological response to a variety of stimuli. The NF‑κB pathway has served as a paradigm for analyzing the impact of the covalent protein modifier ubiquitin on signal transduction. The discovery in the early 1990s that degradation of cytosolic...

The interplay between ubiquitin (Ub) family modifiers creates a regulatory network of Ub family proteins which is essential for cell growth and differentiation. One of the best studied crosstalks between Ub family modifiers is the stimulation of ubiquitination by Nedd8 (neural precursor cell...

Attachment of ubiquitin and ubiquitin‑like proteins to cellular targets represents a fundamental regulatory strategy within eukaryotes and exhibits remarkably pleiotropic effects on cell function. These posttranslational modifications share a common mechanism comprised of three steps: an...

Removal of ubiquitin from modified proteins is an important process to regulate the ubiquitin system. Roughly 100 dedicated enzymes for this purpose, the deubiquitinases, exist in human cells and are intricately involved in a wide variety of cellular processes, although many enzymes remain...

The regulation of a variety of cellular processes, such as endocytosis, DNA‑repair or signal transduction relies on the inducible modification of proteins with Ubiquitin (Ub). Ub‑receptors, i.e., effector proteins carrying Ub‑binding domains (UBDs), recognize ubiquitinated proteins and...

Sumoylation, the covalent attachment of SUMO peptide to cellular proteins, is an essential regulator of protein function involved in a wide range of cellular events. Deregulation of the SUMO pathway is implicated in the pathogenesis of several diseases, so it is important to understand how...

This chapter describes the identification of the first prokaryotic ubiquitin‑like protein modifier, Pup, which covalently attaches to proteins to target them for destruction by a bacterial proteasome in a manner akin to ubiquitin in eukaryotes. Despite using a proteasome as the end point for...

Ubiquitin and SUMO are structurally related protein modifiers that are covalently attached to lysine residues of target proteins. While ubiquitin is traditionally known as a signal for proteasomal degradation, its nondegradative actions are equally important in the control of cellular key...

The ubiquitin‑like modifier FAT10 (HLA‑F adjacent transcript 10) is the only ubiquitin‑like modifier known, which apart from ubiquitin, directly targets proteins to proteasomal degradation. The covalent linkage of ubiquitin or other ubiquitin‑like modifiers (ULM) to specific substrates...

The Cullin‑RING ubiquitin ligase (CRL) family, which may number as many as 350 different enzymes, has an enormous impact on cellular regulation. CRL enzymes regulate cell biology by conjugating ubiquitin onto target proteins that are involved in a multitude of processes. In most cases this...

The small ubiquitin‑related modifier (SUMO) is a versatile cellular tool to modulate a protein’s function. SUMO modification is a reversible process analogous to ubiquitylation. The consecutive actions of E1, E2 and E3 enzymes catalyze the attachment of SUMO to target proteins, while...

Ubiquitin chains are assembled, when a ubiquitin is connected to one of the seven Lys residues or the amino‑terminus of a ubiquitin molecule already attached to a substrate. K48‑linked ubiquitin chains target proteins for degradation by the 26S proteasome, while those chains connected...

ISG15 is an interferon‑induced ubiquitin‑like protein (Ubl) that has antiviral properties. The core E1, E2 and E3 enzymes for conjugation of human ISG15 are Ube1L, UbcH8 and Herc5, all of which are induced at the transcriptional level by type 1 interferon signaling. Several proteomics...

Ubiquitylation is a protein modification mechanism, which is found in a multitude of cellular processes like DNA repair and replication, cell signaling, intracellular trafficking and also, very prominently, in selective protein degradation. One specific protein degradation event in the cell...