Advances in virus research, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 38
Published: Jan. 1, 2024
Language: Английский
Cells, Journal Year: 2023, Volume and Issue: 13(1), P. 29 - 29
Published: Dec. 22, 2023
Ubiquitination is a reversible post-translational modification based on the chemical addition of ubiquitin to proteins with regulatory effects various signaling pathways. can alter molecular functions tagged substrates respect protein turnover, biological activity, subcellular localization or protein–protein interaction. As result, wide variety cellular processes are under ubiquitination-mediated control, contributing maintenance homeostasis. It follows that dysregulation ubiquitination reactions plays relevant role in pathogenic states human diseases such as neurodegenerative diseases, immune-related pathologies and cancer. In recent decades, enzymes ubiquitin–proteasome system (UPS), including E3 ligases deubiquitinases (DUBs), have attracted attention novel druggable targets for development new anticancer therapeutic approaches. This perspective article summarizes peculiarities shared by involved reaction which, when deregulated, lead tumorigenesis. Accordingly, an overview main pharmacological interventions targeting UPS clinical use still trials provided, also highlighting limitations efficacy these Therefore, attempts circumvent drug resistance side well UPS-related emerging technologies therapeutics discussed.
Language: Английский
Citations
29
PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(2), P. e1011186 - e1011186
Published: Feb. 21, 2023
Epstein-Barr virus (EBV) has developed effective strategies to evade host innate immune responses. Here we reported on mitigation of type I interferon (IFN) production by EBV deubiquitinase (DUB) BPLF1 through cGAS-STING and RIG-I-MAVS pathways. The two naturally occurring forms exerted potent suppressive effect cGAS-STING-, RIG-I- TBK1-induced IFN production. observed suppression was reversed when DUB domain rendered catalytically inactive. activity also facilitated infection counteracting cGAS-STING- TBK1-mediated antiviral defense. associated with STING act as an targeting its K63-, K48- K27-linked ubiquitin moieties. catalyzed removal K63- K48-linked chains TBK1 kinase. required for IRF3 dimerization. Importantly, in cells stably carrying genome that encodes a inactive BPLF1, the failed suppress upon activation cGAS STING. This study demonstrated antagonism mediated DUB-dependent deubiquitination leading signaling.
Language: Английский
Citations
24
Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(16)
Published: April 9, 2024
Mosquito-borne flaviviruses such as dengue (DENV) and Zika (ZIKV) cause hundreds of millions infections annually. The single-stranded RNA genome is translated into a polyprotein, which cleaved equally individual functional proteins. While structural proteins are packaged progeny virions released, most the nonstructural remain intracellular could become cytotoxic if accumulated over time. However, mechanism by maintained at levels optimal for cellular fitness viral replication remains unknown. Here, we identified that ubiquitin E3 ligase HRD1 essential in both mammalian hosts mosquitoes. directly interacts with flavivirus NS4A ubiquitylates conserved lysine residue ER-associated degradation. This avoids excessive accumulation NS4A, otherwise interrupts expression processed ER. Furthermore, small-molecule inhibitor named LS-102 effectively DENV2 infection mice Aedes aegypti mosquitoes, significantly disturbs DENV transmission from infected to mosquitoes owing reduced viremia. Taken together, this study demonstrates have evolved sophisticated exploit ubiquitination system balance homeostasis their own advantage provides potential therapeutic target interrupt transmission.
Language: Английский
Citations
7
Autophagy, Journal Year: 2024, Volume and Issue: 20(9), P. 1968 - 1983
Published: May 31, 2024
Many bacterial pathogens have evolved effective strategies to interfere with the ubiquitination network evade clearance by innate immune system. Here, we report that OTUB1, one of most abundant deubiquitinases (DUBs) in mammalian cells, is subjected both canonical and noncanonical during Legionella pneumophila infection. The effectors SidC SdcA catalyze OTUB1 at multiple lysine residues, resulting its association a Legionella-containing vacuole. Lysine promotes interactions between DEPTOR, an inhibitor MTORC1 pathway, thus suppressing signaling. inhibition leads suppression host protein synthesis promotion macroautophagy/autophagy L. In addition, members SidE family (SidEs) induce phosphoribosyl (PR)-linked Ser16 Ser18 block DUB activity. levels serine are further regulated function antagonize activities SidC, SidEs, including Lem27, DupA, DupB, SidJ SdjA. Our study reveals effectors-mediated complicated mechanism regulating activity DUB.
Language: Английский
Citations
6
Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)
Published: Jan. 24, 2025
Language: Английский
Citations
0
Mycology: An International Journal on Fungal Biology, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 13
Published: Feb. 3, 2025
Language: Английский
Citations
0
Current Clinical Microbiology Reports, Journal Year: 2025, Volume and Issue: 12(1)
Published: Feb. 22, 2025
Language: Английский
Citations
0
Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)
Published: March 31, 2025
Ubiquitination plays vital roles in modulating pathogen-host cell interactions. RNF213, a E3 ligase, can catalyze the ubiquitination of lipopolysaccharide (LPS) and is crucial for antibacterial immunity mammals. Shigella flexneri, an LPS-containing pathogenic bacterium, has developed mechanisms to evade host defenses during infection. However, precise strategies by which S. flexneri circumvents RNF213-mediated remain poorly understood. Here, through comprehensive biochemical, structural cellular analyses, we reveal that effector IpaH1.4 directly target human RNF213 via specific interaction between LRR domain RING mediate proteasomal degradation cells. Furthermore, determine cryo-EM structure crystal LRR/RNF213 complex, elucidating molecular mechanism underlying recognition IpaH1.4. Finally, our based functional assays demonstrate targeting promotes proliferation within infected In summary, work uncovers unprecedented strategy employed subvert key immune factor thereby facilitating bacterial invasion. player fighting against various invasive pathogens authors show use its immunity.
Language: Английский
Citations
0
Current Opinion in Immunology, Journal Year: 2023, Volume and Issue: 84, P. 102368 - 102368
Published: July 12, 2023
Language: Английский
Citations
9
PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(3), P. e1012112 - e1012112
Published: March 20, 2024
Viruses are encapsidated mobile genetic elements that rely on host cells for replication. Several cytoplasmic RNA viruses synthesize proteins and/or RNAs translocate to infected cell nuclei. However, the underlying mechanisms and role(s) of cytoplasmic—nuclear trafficking unclear. We demonstrate infection small brown planthoppers with rice stripe virus (RSV), a negarnaviricot virus, results in K63-linked polyubiquitylation RSV’s nonstructural protein 3 (NS3) at residue K127 by RING ubiquitin ligase (E3) LsRING. In turn, ubiquitylation leads NS3 from cytoplasm nucleus, where regulates primary miRNA pri-miR-92 processing through manipulation microprocessor complex, resulting accumulation upregulated lst-miR-92. show lst-miR-92 expression fibrillin 2, an extracellular matrix protein, thereby increasing RSV loads. Our highlight intranuclear, cytoplasmic, components promote its own replication insect vector.
Language: Английский
Citations
3