Ubiquitin and Ubiquitin-Like Proteins: From Molecular Mechanisms to Human Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (15 November 2023) | Viewed by 8135

Special Issue Editors

1. Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
2. Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, 1459 Laney Walker Blvd, Augusta, GA 30912, USA
Interests: protein post-translational modification; ubiquitin; ubiquitin-like proteins; protein degradation; proteasome; autophagy; cardiomyopathy; heart failure

E-Mail Website
Co-Guest Editor
LSU Health Sciences Center—Shreveport, Shreveport, LA, USA
Interests: mitochondrial metabolism; lipid metabolism; autophagy; heart failure

Special Issue Information

Dear Colleagues,

Recent advances in genome- and transcriptome-wide measurements at either single-cell levels or tissue levels have significantly improved our understanding of molecular mechanisms underlying tissue homeostasis and disease progression. However, increasing evidence has revealed a remarkable discordance between mRNA and protein levels in nearly all tested tissues, calling for more research attention on post-translational mechanisms controlling cellular processes and pathophysiological events. Ubiquitin and ubiquitin-like proteins are evolutionarily highly conserved small protein modifiers that can reversibly modify diverse cellular substrates via a similar E1-E2-E3 enzymatic cascade. Such modifications can conjugate one single or a chain of protein modifier moieties to target proteins. Conceptually, these modifications can have subtle or drastic effects on the protein targets’ stability, activity, intracellular distribution, and interaction with DNA and protein partners. Through either fine-tuning or significantly altering the protein's function, ubiquitin and ubiquitin-like protein-mediated modifications are emerging as novel mechanisms regulating a wide spectrum of cellular processes and biological events.  In this Special Issue, we seek articles that enhance our understanding of how ubiquitin and ubiquitin-like proteins regulate protein function and impact health and disease. Original research articles or reviews centered on ubiquitin and ubiquitin-like proteins are of interest to this Special Issue.   

Dr. Huabo Su
Dr. Md. Shenuarin Bhuiyan
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • ubiquitin
  • ubiquitin-like protein
  • protein modification
  • protein degradation

Published Papers (5 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

13 pages, 6607 KiB  
Article
Ufmylation of UFBP1 Is Dispensable for Endoplasmic Reticulum Stress Response, Embryonic Development, and Cardiac and Intestinal Homeostasis
by Varsha Tandra, Travis Anderson, Juan D. Ayala, Neal L. Weintraub, Nagendra Singh, Honglin Li and Jie Li
Cells 2023, 12(15), 1923; https://doi.org/10.3390/cells12151923 - 25 Jul 2023
Viewed by 1228
Abstract
Protein modification by ubiquitin fold modifier 1 (UFM1), termed ufmylation, regulates various physiological and pathological processes. Among emerging UFM1 targets, UFM1 binding protein 1 (UFBP1) is the first identified ufmylation substrate. Recent clinical and animal studies have demonstrated the pivotal roles of UFBP1 [...] Read more.
Protein modification by ubiquitin fold modifier 1 (UFM1), termed ufmylation, regulates various physiological and pathological processes. Among emerging UFM1 targets, UFM1 binding protein 1 (UFBP1) is the first identified ufmylation substrate. Recent clinical and animal studies have demonstrated the pivotal roles of UFBP1 in development, hematopoiesis, intestinal homeostasis, chondrogenesis, and neuronal development, which has been linked to its function in maintaining endoplasmic reticulum (ER) homeostasis. However, the importance of UFBP1 ufmylation in these cellular and physiological processes has yet to be determined. It has been proposed that ufmylation of lysine 268 (267 in humans) in UFBP1 plays a critical role in mediating the effects of the ufmylation pathway. In this study, we for the first time probe the pathophysiological significance of UFBP1 ufmylation in vivo by creating and characterizing a mouse UFBP1 knockin (KI) model in which the lysine 268 of UFBP1, the amino acid accepting UFM1, was mutated to arginine. Our results showed that the K268R mutation reduced the total ufmylated proteins without altering the expression levels of individual ufmylation enzymes in mouse embryonic fibroblasts. The K268R mutation did not alter ER stress–stimuli–induced ER stress signaling or cell death in mouse embryonic fibroblasts. The homozygous KI mice were viable and morphologically indistinguishable from their littermate wild–type controls up to one year of age. Serial echocardiography revealed no cardiac functional impairment of the homozygous KI mice. Furthermore, the homozygous KI mice exhibited the same susceptibility to dextran sulfate sodium (DSS) –induced colitis as wild-type mice. Taken together, these results suggest that UFBP1 K268 is dispensable for ER stress response, embryonic development, cardiac homeostasis under physiological conditions, and intestinal homeostasis under pathological conditions. Our studies call for future investigations to understand the biological function of UFBP1 ufmylation and offer a new mouse model to determine the roles of UFBP1 ufmylation in different tissues under stress conditions. Full article
Show Figures

Figure 1

Review

Jump to: Research

18 pages, 766 KiB  
Review
Emerging Roles of Cullin-RING Ubiquitin Ligases in Cardiac Development
by Josue Zambrano-Carrasco, Jianqiu Zou, Wenjuan Wang, Xinghui Sun, Jie Li and Huabo Su
Cells 2024, 13(3), 235; https://doi.org/10.3390/cells13030235 - 26 Jan 2024
Viewed by 1017
Abstract
Heart development is a spatiotemporally regulated process that extends from the embryonic phase to postnatal stages. Disruption of this highly orchestrated process can lead to congenital heart disease or predispose the heart to cardiomyopathy or heart failure. Consequently, gaining an in-depth understanding of [...] Read more.
Heart development is a spatiotemporally regulated process that extends from the embryonic phase to postnatal stages. Disruption of this highly orchestrated process can lead to congenital heart disease or predispose the heart to cardiomyopathy or heart failure. Consequently, gaining an in-depth understanding of the molecular mechanisms governing cardiac development holds considerable promise for the development of innovative therapies for various cardiac ailments. While significant progress in uncovering novel transcriptional and epigenetic regulators of heart development has been made, the exploration of post-translational mechanisms that influence this process has lagged. Culling-RING E3 ubiquitin ligases (CRLs), the largest family of ubiquitin ligases, control the ubiquitination and degradation of ~20% of intracellular proteins. Emerging evidence has uncovered the critical roles of CRLs in the regulation of a wide range of cellular, physiological, and pathological processes. In this review, we summarize current findings on the versatile regulation of cardiac morphogenesis and maturation by CRLs and present future perspectives to advance our comprehensive understanding of how CRLs govern cardiac developmental processes. Full article
Show Figures

Figure 1

28 pages, 2591 KiB  
Review
Paralogue-Specific Roles of SUMO1 and SUMO2/3 in Protein Quality Control and Associated Diseases
by Wei Wang and Michael J. Matunis
Cells 2024, 13(1), 8; https://doi.org/10.3390/cells13010008 - 20 Dec 2023
Viewed by 1194
Abstract
Small ubiquitin-related modifiers (SUMOs) function as post-translational protein modifications and regulate nearly every aspect of cellular function. While a single ubiquitin protein is expressed across eukaryotic organisms, multiple SUMO paralogues with distinct biomolecular properties have been identified in plants and vertebrates. Five SUMO [...] Read more.
Small ubiquitin-related modifiers (SUMOs) function as post-translational protein modifications and regulate nearly every aspect of cellular function. While a single ubiquitin protein is expressed across eukaryotic organisms, multiple SUMO paralogues with distinct biomolecular properties have been identified in plants and vertebrates. Five SUMO paralogues have been characterized in humans, with SUMO1, SUMO2 and SUMO3 being the best studied. SUMO2 and SUMO3 share 97% protein sequence homology (and are thus referred to as SUMO2/3) but only 47% homology with SUMO1. To date, thousands of putative sumoylation substrates have been identified thanks to advanced proteomic techniques, but the identification of SUMO1- and SUMO2/3-specific modifications and their unique functions in physiology and pathology are not well understood. The SUMO2/3 paralogues play an important role in proteostasis, converging with ubiquitylation to mediate protein degradation. This function is achieved primarily through SUMO-targeted ubiquitin ligases (STUbLs), which preferentially bind and ubiquitylate poly-SUMO2/3 modified proteins. Effects of the SUMO1 paralogue on protein solubility and aggregation independent of STUbLs and proteasomal degradation have also been reported. Consistent with these functions, sumoylation is implicated in multiple human diseases associated with disturbed proteostasis, and a broad range of pathogenic proteins have been identified as SUMO1 and SUMO2/3 substrates. A better understanding of paralogue-specific functions of SUMO1 and SUMO2/3 in cellular protein quality control may therefore provide novel insights into disease pathogenesis and therapeutic innovation. This review summarizes current understandings of the roles of sumoylation in protein quality control and associated diseases, with a focus on the specific effects of SUMO1 and SUMO2/3 paralogues. Full article
Show Figures

Figure 1

11 pages, 1749 KiB  
Review
The Highs and Lows of FBXW7: New Insights into Substrate Affinity in Disease and Development
by Claire C. de la Cova
Cells 2023, 12(17), 2141; https://doi.org/10.3390/cells12172141 - 24 Aug 2023
Viewed by 1295
Abstract
FBXW7 is a critical regulator of cell cycle, cell signaling, and development. A highly conserved F-box protein and component of the SKP1–Cullin–F-box (SCF) complex, FBXW7 functions as a recognition subunit within a Cullin–RING E3 ubiquitin ligase responsible for ubiquitinating substrate proteins and targeting [...] Read more.
FBXW7 is a critical regulator of cell cycle, cell signaling, and development. A highly conserved F-box protein and component of the SKP1–Cullin–F-box (SCF) complex, FBXW7 functions as a recognition subunit within a Cullin–RING E3 ubiquitin ligase responsible for ubiquitinating substrate proteins and targeting them for proteasome-mediated degradation. In human cells, FBXW7 promotes degradation of a large number of substrate proteins, including many that impact disease, such as NOTCH1, Cyclin E, MYC, and BRAF. A central focus for investigation has been to understand the molecular mechanisms that allow the exquisite substrate specificity exhibited by FBXW7. Recent work has produced a clearer understanding of how FBXW7 physically interacts with both high-affinity and low-affinity substrates. We review new findings that provide insights into the consequences of “hotspot” missense mutations of FBXW7 that are found in human cancers. Finally, we discuss how the FBXW7–substrate interaction, and the kinases responsible for substrate phosphorylation, contribute to patterned protein degradation in C. elegans development. Full article
Show Figures

Figure 1

25 pages, 2042 KiB  
Review
Targeted Protein Degradation: Principles and Applications of the Proteasome
by Yosup Kim, Eun-Kyung Kim, Yoona Chey, Min-Jeong Song and Ho Hee Jang
Cells 2023, 12(14), 1846; https://doi.org/10.3390/cells12141846 - 13 Jul 2023
Cited by 3 | Viewed by 2734
Abstract
The proteasome is a multi-catalytic protease complex that is involved in protein quality control via three proteolytic activities (i.e., caspase-, trypsin-, and chymotrypsin-like activities). Most cellular proteins are selectively degraded by the proteasome via ubiquitination. Moreover, the ubiquitin–proteasome system is a critical process [...] Read more.
The proteasome is a multi-catalytic protease complex that is involved in protein quality control via three proteolytic activities (i.e., caspase-, trypsin-, and chymotrypsin-like activities). Most cellular proteins are selectively degraded by the proteasome via ubiquitination. Moreover, the ubiquitin–proteasome system is a critical process for maintaining protein homeostasis. Here, we briefly summarize the structure of the proteasome, its regulatory mechanisms, proteins that regulate proteasome activity, and alterations to proteasome activity found in diverse diseases, chemoresistant cells, and cancer stem cells. Finally, we describe potential therapeutic modalities that use the ubiquitin–proteasome system. Full article
Show Figures

Figure 1

Back to TopTop