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Deubiquitylases in Developmental Ubiquitin Signaling and Congenital Diseases

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Deubiquitylases in Developmental Ubiquitin Signaling and Congenital Diseases Cell Death & Differentiation (2021) 28:538–556 https://doi.org/10.1038/s41418-020-00697-5 REVIEW ARTICLE Deubiquitylases in developmental ubiquitin signaling and congenital diseases 1 1,2 1 Mohammed A. Basar ● David B. Beck ● Achim Werner Received: 16 October 2020 / Revised: 20 November 2020 / Accepted: 24 November 2020 / Published online: 17 December 2020 This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020 Abstract Metazoan development from a one-cell zygote to a fully formed organism requires complex cellular differentiation and communication pathways. To coordinate these processes, embryos frequently encode signaling information with the small protein modifier ubiquitin, which is typically attached to lysine residues within substrates. During ubiquitin signaling, a three-step enzymatic cascade modifies specific substrates with topologically unique ubiquitin modifications, which mediate changes in the substrate’s stability, activity, localization, or interacting proteins. Ubiquitin signaling is critically regulated by deubiquitylases (DUBs), a class of ~100 human enzymes that oppose the conjugation of ubiquitin. DUBs control many essential cellular functions and various aspects of human physiology and development. Recent genetic studies have fi 1234567890();,: 1234567890();,: identi ed mutations in several DUBs that cause developmental disorders. Here we review principles controlling DUB activity and substrate recruitment that allow these enzymes to regulate ubiquitin signaling during development. We summarize key mechanisms of how DUBs control embryonic and postnatal differentiation processes, highlight developmental disorders that are caused by mutations in particular DUB members, and describe our current understanding of how these mutations disrupt development. Finally, we discuss how emerging tools from human disease genetics will enable the identification and study of novel congenital disease-causing DUBs. Facts recruitment to allow DUBs to integrate signals during development and coordinate developmental cell-fate ● Deubiquitylases (DUBs) are a class of ~100 human decision. enzymes that regulate ubiquitin signaling by proces- ● DUBs regulate gene expression (through deubiquitylat- sing ubiquitin precursors, hydrolyzing ubiquitin ing histones and modulating the stability of chromatin chains, and cleaving ubiquitin modifications from regulators/transcription factors) and signaling pathways substrates. to control metazoan development. ● Intricate regulatory mechanisms ensure spatial and ● Mutations in particular DUBs cause developmental temporal regulation of DUB activity and substrate disorders, but the molecular mechanisms and cognate substrates or E3 ligases are often unknown. ● Many DUBs are intolerant to haploinsufficiency and missense mutations in the general human population, suggesting that their dysregulation likely causes devel- opmental diseases. Edited by G. Melino * Achim Werner [email protected] Open questions 1 Stem Cell Biochemistry Unit, National Institute of Dental and ● How are specific DUBs regulated during embryonic and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA postnatal development to achieve their functions in cell- fate determination? 2 Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National ● What are the mechanisms and substrates of DUBs Institutes of Health, Bethesda, MD 20892, USA whose mutations underlie developmental diseases? Deubiquitylases in developmental ubiquitin signaling and congenital diseases 539 ● Which other DUBs cause developmental diseases? Can ubiquitin signals, which are covalently linked to substrates we utilize tools from human genetics to identify these and recognized and interpreted by various effector proteins DUBs and study their (patho-)physiological functions (Fig. 1A) [4–6]. Research in recent decades has elucidated and mechanisms? key principles of this ubiquitin code [4]. Substrates can either be modified with ubiquitin monomers or with struc- turally distinct ubiquitin polymers that are linked via the N Introduction: the ubiquitin code and DUBs in terminus or one of the seven internal lysine residues (K6, early development K11, K27, K29, K33, K48, K63). These ubiquitin polymers can be homotypic (chains with only one linkage type) or During metazoan development, stem cells of the embryo heterotypic (chains with at least 2 different linkage types) undergo self-renewal, commit to differentiation programs, [7]. Mono- or multi-monoubiquitylation of substrates often and produce and react to signaling molecules to ensure result in changes in the interaction landscape of the mod- proper formation of specialized cell types, tissues, and ified protein and play important roles during e.g., tran- organs. The precise execution of these processes is often scription, translation, and endosomal sorting [8–11]. controlled by ubiquitylation, an essential posttranslational Modification of substrates with homotypic and heterotypic modification (PTM) that regulates the stability, activity, ubiquitin polymers elicits various downstream effects, localization, or interaction landscape of substrates [1–3]. which depend on the linkage type(s) and architecture of the The differential outcomes of ubiquitylation are accom- ubiquitin chain. Well established examples with relevance plished by elaborate enzymatic cascades that synthesize to this review include homotypic K11- or K48-linked chains Fig. 1 Overview of how ubiquitin signaling regulates develop- controls cellular behavior during many physiological processes, mental cell-fate decisions and cleavage modes of DUBs. A To including development. DUBs are important regulators of this ubi- initiate ubiquitin signaling, an enzymatic cascade, consisting of ubi- quitin code by reversing ubiquitin modifications, thus modulating or quitin E1 activating, E2 conjugating, and E3 ligating enzymes, dec- terminating signaling. B Cartoons depicting different position- and orates substrates with topologically different ubiquitin modifications. linkage-specific cleavage modes by which DUBs can act on their Effector proteins containing various ubiquitin-binding domains substrates. The yellow arrow indicates the peptide/isopeptide bond that (UBDs) interpret the ubiquitin signals and mediate changes in the is hydrolyzed in each example. substrate activity, stability, localization or interacting proteins. This 540 M. A. Basar et al. that mediate degradation via the 26S proteasome [12, 13], Structural and functional features of DUBs homotypic M1- or K63-linked chains that allow for for- mation of signaling complexes during NF-kB activation DUB families [14, 15] and DNA repair [16–18], and homotypic K63- linked chains that mediate autophagic degradation of pro- Since the discovery of DUBs in the mid-1980s [48–50], tein complexes, aggregates, and damaged organelles [19]. extensive studies have defined them as a structurally diverse Ubiquitylation regulates biological pathways in a highly set of ~100 human proteases that can be divided into two specific and reversible manner, which enables ubiquitin groups according to their enzymatic mechanisms. First, signaling to control cellular behavior and decision-making zinc-dependent JAB1/MPN/MOV34 (JAMM) metallopro- during embryonic development [1, 3]. Specificity is teases (12 human members) and second papain-like cysteine achieved by more than 600 ubiquitin E3 ligases, which bind proteases that, based on their catalytic domain, are further distinct sets of substrates and cooperate with 2 E1 and ~40 subclassified into six families: ubiquitin-specific proteases E2 enzymes to mediate transfer of ubiquitin monomers or (USPs, 56 members), ovarian tumor proteases (OTUs, chains to thousands of cellular substrates [4, 20, 21]. 17 human members), ubiquitin carboxy-terminal hydrolases Reversibility is ensured by ~100 human deubiquitylases (UCHs, 4 human members), the Machado–Joseph disease (DUBs), a family of enzymes that processes ubiquitin pre- proteases (MJDs, 4 human members), and two more cursors, edits chain architecture, or cleaves ubiquitin signals recently identified families, the motif interacting with from substrates. Through these activities, DUBs maintain a ubiquitin-containing novel DUB family (MINDYs [51], 5 functional ubiquitin pool for conjugation and modulate or human members) and zinc finger containing ubiquitin terminate signaling responses [1, 22–24]. peptidase 1 family (ZUP1, 1 human member [52–55]). DUBs can deubiquitylate a broad range of substrates in Eleven of these 99 DUBs have lost critical catalytic residues fundamental cellular processes including transcription, and are thought to be catalytically inactive [56]. translation, cell cycle progression, vesicular trafficking, autophagy, proteasomal degradation, and intracellular DUBs can remove ubiquitin from substrates or signaling to control various aspects of stem cell main- cleave ubiquitin-linkages tenance, differentiation, and development [1, 3, 25–30]. Consistent with these essential functions, genetic deletion Several in-depth discussions on DUB enzymology, struc- of a number of DUBs are embryonic, early postnatal, or ture, and substrate specificity have recently been published perinatal lethal in mice (examples discussed in this and we refer interested readers to these seminal reviews review include USP7 [31], USP8 [32], USP9X [33, 34], [22, 27, 57–60]. To provide the mechanistic framework for
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