Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

MedComm, Journal Year: 2023, Volume and Issue: 4(3)

Published: May 2, 2023

Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on backbones amino acid side chains proteins and expand diversity proteins, which provides basis for emergence organismal complexity. To date, more than 650 types protein modifications, such as most well-known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short-chain long-chain acylation redox irreversible have been described, inventory is still increasing. By changing conformation, localization, activity, stability, charges, interactions with other biomolecules, PTMs ultimately alter phenotypes biological processes cells. The homeostasis important human health. Abnormal may cause changes in properties loss functions, are closely related occurrence development various diseases. In this review, we systematically introduce characteristics, regulatory mechanisms, functions health addition, therapeutic prospects diseases by targeting associated enzymes also summarized. This work will deepen understanding promote discovery diagnostic prognostic markers drug targets

Language: Английский

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Protein acylation: mechanisms, biological functions and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 29, 2022

Metabolic reprogramming is involved in the pathogenesis of not only cancers but also neurodegenerative diseases, cardiovascular and infectious diseases. With progress metabonomics proteomics, metabolites have been found to affect protein acylations through providing acyl groups or changing activities acyltransferases deacylases. Reciprocally, acylation key cellular processes relevant physiology such as stability, subcellular localization, enzyme activity, transcriptional protein-protein interactions protein-DNA interactions. Herein, we summarize functional diversity mechanisms eight kinds nonhistone physiological progression several We highlight recent development inhibitors for acyltransferase, deacylase, reader proteins their potential applications drug discovery.

Language: Английский

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SARS-CoV-2 and the Host Cell: A Tale of Interactions

Frontiers in Virology, Journal Year: 2022, Volume and Issue: 1

Published: Jan. 12, 2022

The ability of a virus to spread between individuals, its replication capacity and the clinical course infection are macroscopic consequences multifaceted molecular interaction viral components with host cell. heavy impact COVID-19 on world population, economics sanitary systems calls for therapeutic prophylactic solutions that require deep characterization interactions occurring cells. Unveiling how SARS-CoV-2 engages factors throughout life cycle is therefore fundamental understand pathogenic mechanisms underlying design antiviral therapies strategies. Two years into pandemic, this review provides an overview interplay cell, focus machinery compartments pivotal cellular response. Starting cell surface, following replicative through entry pathways, survival in cytoplasm, egress from infected unravels complex network highlighting knowledge has potential set basis development innovative

Language: Английский

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Protein lipidation in health and disease: molecular basis, physiological function and pathological implication

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 15, 2024

Abstract Posttranslational modifications increase the complexity and functional diversity of proteins in response to complex external stimuli internal changes. Among these, protein lipidations which refer lipid attachment are prominent, primarily encompassing five types including S-palmitoylation, N-myristoylation, S-prenylation, glycosylphosphatidylinositol (GPI) anchor cholesterylation. Lipid plays an essential role regulation trafficking, localisation, stability, conformation, interactions signal transduction by enhancing hydrophobicity. Accumulating evidence from genetic, structural, biomedical studies has consistently shown that lipidation is pivotal broad physiological functions inextricably linked a variety diseases. Decades dedicated research have driven development wide range drugs targeting lipidation, several agents been developed tested preclinical clinical studies, some which, such as asciminib lonafarnib FDA-approved for therapeutic use, indicating represents promising strategy. Here, we comprehensively review known regulatory enzymes catalytic mechanisms various types, outline impact on physiology disease, highlight potential targets progress, aiming provide comprehensive reference future research.

Language: Английский

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TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 4, 2024

Abstract Viruses, as opportunistic intracellular parasites, hijack the cellular machinery of host cells to support their survival and propagation. Numerous viral proteins are subjected host-mediated post-translational modifications. Here, we demonstrate that SARS-CoV-2 nucleocapsid protein (SARS2-NP) is SUMOylated on lysine 65 residue, which efficiently mediates SARS2-NP’s ability in homo-oligomerization, RNA association, liquid-liquid phase separation (LLPS). Thereby innate antiviral immune response suppressed robustly. These roles can be achieved through intermolecular association between SUMO conjugation a newly identified SUMO-interacting motif SARS2-NP. Importantly, widespread SARS2-NP R203K mutation gains novel site SUMOylation further increases LLPS immunosuppression. Notably, E3 ligase TRIM28 responsible for catalyzing SUMOylation. An interfering peptide targeting interaction was screened out block LLPS, consequently inhibit replication rescue immunity. Collectively, these data critical virulence, therefore provide strategy antagonize SARS-CoV-2.

Language: Английский

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The complete and fully-phased diploid genome of a male Han Chinese

Cell Research, Journal Year: 2023, Volume and Issue: 33(10), P. 745 - 761

Published: July 14, 2023

Since the release of complete human genome, priority genomic study has now been shifting towards closing gaps in ethnic diversity. Here, we present a fully phased and well-annotated diploid genome from Han Chinese male individual (CN1), which assemblies both haploids achieve telomere-to-telomere (T2T) level. Comparison this with CHM13 haploid T2T revealed significant variations centromere. Outside centromere, discovered 11,413 structural variations, including numerous novel ones. We also detected thousands CN1 alleles that have accumulated high substitution rates few under positive selection East Asian population. Further, found outperforms as reference mapping variant calling for population owing to distinct variants two references. SNP large cohort 8869 genomes using respectively showed bias profoundly impacts rare calling, nearly 2 million SNPs miss-called different genomes. Finally, applying reference, 5.80 Mb 4.21 putative introgression sequences Neanderthal Denisovan, respectively, many specific ones undetected reference. Our analyses reveal advances studies paleo-genomic studies. This will serve an alternative future on

Language: Английский

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Metabolic alterations upon SARS-CoV-2 infection and potential therapeutic targets against coronavirus infection

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: June 7, 2023

Abstract The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection has become a global pandemic due to the high viral transmissibility and pathogenesis, bringing enormous burden our society. Most patients infected are asymptomatic or have mild symptoms. Although only small proportion of progressed severe COVID-19 with symptoms including acute respiratory distress syndrome (ARDS), disseminated coagulopathy, cardiovascular disorders, is accompanied mortality rates near 7 million deaths. Nowadays, effective therapeutic patterns for still lacking. It been extensively reported that host metabolism plays essential roles in various physiological processes during virus infection. Many viruses manipulate avoid immunity, facilitate their own replication, initiate pathological response. Targeting interaction between holds promise developing strategies. In this review, we summarize discuss recent studies dedicated uncovering role life cycle aspects entry, assembly, pathogenesis an emphasis on glucose lipid metabolism. Microbiota long also discussed. Ultimately, recapitulate metabolism-modulating drugs repurposed statins, ASM inhibitors, NSAIDs, Montelukast, omega-3 fatty acids, 2-DG, metformin.

Language: Английский

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Protein post-translational modification in SARS-CoV-2 and host interaction

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 13, 2023

SARS-CoV-2 can cause lung diseases, such as pneumonia and acute respiratory distress syndrome, multi-system dysfunction. Post-translational modifications (PTMs) related to are conservative pathogenic, the common PTMs glycosylation, phosphorylation, acylation. The glycosylation of mainly occurs on spike (S) protein, which mediates entry virus into cells through interaction with angiotensin-converting enzyme 2. utilizes glycans cover its epitopes evade immune response S protein. Phosphorylation nucleocapsid (N) protein improves selective binding viral RNA promotes replication transcription, thereby increasing load in host. Succinylated N membrane(M) proteins synergistically affect particle assembly. regulates affinity for other genome acetylation. acetylated envelope (E) interacts bromodomain-containing 2/4 influence host response. Both palmitoylation myristoylation sites infectivity. Papain-like protease is a domain NSP3 that dysregulates inflammation by deubiquitination impinges IFN-I antiviral responses deISGylation. Ubiquitination ORF7a inhibits IFN-α signaling blocking STAT2 phosphorylation. methylation inhibit formation stress granules promote RNA, promoting production particles. macrodomain reverse ADP-ribosylation proteins, cascade IFN core, intracellular SARS-CoV-2. On whole, have fundamental roles entry, replication, assembly, Mutations various variants, lead changes at corresponding sites, different biological effects. In this paper, we reviewed effects cells, whose application inform strategies inhibiting infection facilitating treatment vaccine development COVID-19.

Language: Английский

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Palmitoylation of SARS‐CoV‐2 S protein is critical for S‐mediated syncytia formation and virus entry

Journal of Medical Virology, Journal Year: 2021, Volume and Issue: 94(1), P. 342 - 348

Published: Sept. 16, 2021

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the cause of ongoing disease 2019 (COVID‐19) pandemic. The S protein key viral for associating with ACE2, receptor SARS‐CoV‐2. There are many kinds posttranslational modifications in protein. However, detailed mechanism palmitoylation SARS‐CoV‐2 remains to be elucidated. In our current study, we characterized S. Both C15 and cytoplasmic tail were palmitoylated. Fatty acid synthase inhibitor C75 zinc finger DHHC domain‐containing palmitoyltransferase (ZDHHC) 2‐BP reduced Interestingly, was not required plasma membrane targeting but critical S‐mediated syncytia formation pseudovirus particle entry. Overexpression ZDHHC2, ZDHHC3, ZDHHC4, ZDHHC5, ZDHHC8, ZDHHC9, ZDHHC11, ZDHHC14, ZDHHC16, ZDHHC19, ZDHHC20 promoted Furthermore, those ZDHHCs identified associate Our study only reveals also will shed important light into role virus

Language: Английский

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Identification of SARS-CoV-2 Spike Palmitoylation Inhibitors That Results in Release of Attenuated Virus with Reduced Infectivity

Viruses, Journal Year: 2022, Volume and Issue: 14(3), P. 531 - 531

Published: March 4, 2022

The spike proteins of enveloped viruses are transmembrane glycoproteins that typically undergo post-translational attachment palmitate on cysteine residues the cytoplasmic facing tail protein. role protein palmitoylation in virus biogenesis and infectivity is being actively studied as a potential target novel antivirals. Here, we report first five C-terminal cysteine-rich domain SARS-CoV-2 S indispensable for infection, palmitoylation-deficient mutants defective membrane fusion. DHHC9 palmitoyltransferase interacts with palmitoylates ER Golgi knockdown results reduced fusion infection SARS-CoV-2. Two bis-piperazine backbone-based inhibitors inhibit resulting progeny virion particles released infection. This establishes these new intervention strategies against

Language: Английский

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