A new dawn beyond lysine ubiquitination

Nature Chemical Biology, Journal Year: 2022, Volume and Issue: 18(8), P. 802 - 811

Published: July 27, 2022

Language: Английский

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The ubiquitin codes in cellular stress responses

Protein & Cell, Journal Year: 2023, Volume and Issue: 15(3), P. 157 - 190

Published: July 19, 2023

Ubiquitination/ubiquitylation, one of the most fundamental post-translational modifications, regulates almost every critical cellular process in eukaryotes. Emerging evidence has shown that essential components numerous biological processes undergo ubiquitination mammalian cells upon exposure to diverse stresses, from exogenous factors reactions, causing a dazzling variety functional consequences. Various forms ubiquitin signals generated by ubiquitylation events specific milieus, known as codes, constitute an intrinsic part myriad stress responses. These events, leading proteolytic turnover substrates or just switch functionality, initiate, regulate, supervise multiple stress-associated responses, supporting adaptation, homeostasis recovery, and survival stressed cells. In this review, we attempted summarize crucial roles response different environmental intracellular while discussing how stresses modulate system. This review also updates recent advances understanding machinery well responses discusses some important questions may warrant future investigation.

Language: Английский

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The logic of protein post‐translational modifications (PTMs): Chemistry, mechanisms and evolution of protein regulation through covalent attachments

BioEssays, Journal Year: 2024, Volume and Issue: 46(3)

Published: Jan. 21, 2024

Abstract Protein post‐translational modifications (PTMs) play a crucial role in all cellular functions by regulating protein activity, interactions and half‐life. Despite the enormous diversity of modifications, various PTM systems show parallels their chemical catalytic underpinnings. Here, focussing on that involve addition new elements to amino‐acid sidechains, I describe historical milestones fundamental concepts support current understanding PTMs. The survey covers selected key research programmes, including study phosphorylation as regulatory switch, ubiquitylation degradation signal histone functional code. contribution techniques for studying PTMs is also discussed. central part essay explores shared principles strategies observed across diverse systems, together with mechanisms substrate selection, reversibility erasers recognition reader domains. Similarities basic mechanism are highlighted implications final dedicated evolutionary trajectories beginning possible emergence context rivalry prokaryotic world. Together, provides unified perspective world major modifications.

Language: Английский

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Ubiquitylation of BBSome is required for ciliary assembly and signaling

EMBO Reports, Journal Year: 2023, Volume and Issue: 24(4)

Published: Feb. 6, 2023

Abstract Bardet‐Biedl syndrome (BBS) is a ciliopathy characterized by retinal degeneration, obesity, renal abnormalities, postaxial polydactyly, and developmental defects. Genes mutated in BBS encode for components regulators of the BBSome, an octameric complex that controls trafficking cargos receptors within primary cilium. Although both structure function BBSome have been extensively studied, impact ubiquitin signaling on largely unknown. We identify E3 ligase PJA2 as novel resident ciliary compartment regulator BBSome. Upon GPCR‐cAMP stimulation, ubiquitylates subunits. demonstrate ubiquitylation BBS1 at lysine 143 increases stability promotes its binding to BBS3, Arf‐like GTPase protein controlling targeting membrane. Downregulation or expression ubiquitylation‐defective mutant (BBS1 K143R ) affects G‐protein‐coupled (GPCRs) Shh‐dependent gene transcription. Expression vivo impairs cilium formation, embryonic development, photoreceptors' morphogenesis, thus recapitulating phenotype medaka fish model.

Language: Английский

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Epigenetic markers in the embryonal germ cell development and spermatogenesis

Basic and Clinical Andrology, Journal Year: 2023, Volume and Issue: 33(1)

Published: Feb. 23, 2023

Abstract Spermatogenesis is the process of generation male reproductive cells from spermatogonial stem in seminiferous epithelium testis. During spermatogenesis, key spermatogenic events such as cell self-renewal and commitment to meiosis, meiotic recombination, sex chromosome inactivation, followed by cellular chromatin remodeling elongating spermatids occur, leading sperm production. All mentioned are at least partially controlled epigenetic modifications DNA histones. Additionally, during embryonal development primordial germ cells, global reprogramming occurs. In this review, we summarized most important particular stages development, histone proteins, starting ending with histone-to-protamine transition spermiogenesis.

Language: Английский

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Ubiquitin-specific protease 7 (USP7): an emerging drug target for cancer treatment

Expert Opinion on Therapeutic Targets, Journal Year: 2023, Volume and Issue: 27(11), P. 1043 - 1058

Published: Oct. 4, 2023

ABSTRACTIntroduction Ubiquitin-specific protease 7 (USP7) also known as herpesvirus-associated ubiquitin-specific (HAUSP) is a well-characterized cysteine that belongs to the largest subfamily of deubiquitinating enzymes (DUBs). It involved in multiple signaling pathways, some them dysregulated malignant tumors. USP7 inhibition can lead cell growth arrest and apoptosis through tumor promoters stabilization suppressors, making it promising druggable target for cancer therapy.Areas covered This review covers structure USP7, its function pathways relevance cancer, well recent advances future perspectives development inhibitors therapy.Expert opinion Literature reports display antitumor activities inhibitors, both vitro vivo. Nonetheless, none have entered clinical trials so far, highlighting need delve into deeper understanding binding sites more accurate compound screening methods. Despite these challenges, further valuable new approach treatment, including ability address chemoresistance.KEYWORDS: Cancerdeubiquitinasesdrug targetinhibitorsubiquitin-proteasome systemubiquitin-specific 7chemoresistance Article highlights key regulator myriad cellular MDM2/MDMDX-p53, PTEN, Wnt/β-catenin NF-κB.The abnormal expression many types involvement cancer-associated make predictive biomarker pharmacological intervention.The combination other cytotoxic agents may be overcome drug resistance cancers.Some exhibit anticancer effects by boosting anti-tumor immune responses.Although show great potential vivo vitro, challenges still en route approval.List abbreviations Akt=protein kinase BAsn=asparagineAsp=aspartateCID=β-catenin inhibitory domainCRC=colorectal cancerCys=cysteineDAXX=death domain associated proteinDUB=deubiquitinaseE1=ubiquitin-activating enzymeE2=ubiquitin-conjugating enzymeE3=ubiquitin-ligase enzymeFOXP3=forkhead box P3HAUSP=herpesvirus-associated proteaseHDM2=human double minute 2His=histidineIκB=inhibitor NF-κBMDM2=murine 2MDMX=murine XMM=multiple myelomamTor=mammalian rapamycinNEK2=NIMA related 2NF-κB=nuclear factor-kappa BPARP=poly (ADP-ribose) polymerasePD-1=programmed death 1PD-L1=programmed ligand 1PI3K=phosphatidylinositol 3-kinasePROTAC=proteolysis targeting chimeraPTEN=phosphatase tensin homolog deleted on chromosome 10PTM=post-translation modificationRNF=ring finger proteinTeff cells=effector T cellsTRAF=tumor necrosis factor receptor-associated factorTreg cells=regulatory cellsUBL=ubiquitin-like domainUPS=ubiquitin-proteasome systemUSP=ubiquitin-specific proteaseUSP7=ubiquitin-specific 7Declarations interestLD Carreira thanks Portuguese Research Agency FCT – Fundação para Ciência e Tecnologia, I.P., funding individual PhD grant 2022.10811.BD.RI Oliveira I.P. 2021.07538.BD.The authors no relevant affiliations or financial with any organization entity interest conflict subject matter materials discussed manuscript apart from those disclosed.Reviewer disclosuresA reviewer this has disclosed they worked Forma Therapeutics inhibitors. Peer reviewers relationships otherwise disclose.Additional informationFundingThis paper was supported FCT—Fundação

Language: Английский

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Excess filaggrin in keratinocytes is removed by extracellular vesicles to prevent premature death and this mechanism can be hijacked by Staphylococcus aureus in a TLR2‐dependent fashion

Journal of Extracellular Vesicles, Journal Year: 2023, Volume and Issue: 12(6)

Published: June 1, 2023

Abstract Filaggrin (FLG) protein is indispensable for multiple aspects of the epidermal barrier function but its accumulation in a monomeric filaggrin form may initiate premature keratinocytes death; it unclear how levels are controlled before formation storing keratohyalin granules. Here we show that keratinocyte‐secreted small extracellular vesicles (sEVs) contain filaggrin‐related cargo providing route eliminating excess from keratinocytes; blocking sEV release has cytotoxic effects on those cells. Filaggrin‐containing sEVs found plasma both healthy individuals and atopic dermatitis patients. Staphylococcus aureus (S. aureus) enhances packaging secretion filaggrin‐relevant products within enhanced export via TLR2‐mediated mechanism which also linked to ubiquitination process. This removal system, preventing keratinocyte death dysfunction, exploited by S. promotes elimination skin could help safeguard bacterial growth.

Language: Английский

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Target protein degradation by protacs: A budding cancer treatment strategy

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 250, P. 108525 - 108525

Published: Sept. 9, 2023

Language: Английский

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A critical discussion on the relationship between E3 ubiquitin ligases, protein degradation, and skeletal muscle wasting: it’s not that simple

AJP Cell Physiology, Journal Year: 2023, Volume and Issue: 325(6), P. C1567 - C1582

Published: Nov. 13, 2023

Ubiquitination is an important post-translational modification (PTM) for protein substrates, whereby ubiquitin added to proteins through the coordinated activity of activating (E1), ubiquitin-conjugating (E2), and ligase (E3) enzymes. The E3s provide key functions in recognition specific substrates be ubiquitinated aid determining their proteolytic or nonproteolytic fates, which has led study as indicators altered cellular processes. MuRF1 MAFbx/Atrogin-1 were two first E3 ligases identified being upregulated a range different skeletal muscle atrophy models. Since discovery, expression these often been studied surrogate measure changes bulk degradation rates. However, emerging evidence highlighted dynamic complex regulation proteasome system (UPS) demonstrated that ubiquitination not necessarily equivalent degradation. These observations highlight potential challenges quantifying markers rates activation. This perspective examines usefulness monitoring settings atrophy. Specific questions remain unanswered within field are also identified, encourage pursuit new research will critical moving forward our understanding molecular mechanisms govern function muscle.

Language: Английский

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Specificity profiling of deubiquitylases against endogenously generated ubiquitin-protein conjugates

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(7), P. 1349 - 1362.e5

Published: May 28, 2024

Language: Английский

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