FBXW8 suppresses PDCoV proliferation via the NPD52-dependent autophagic degradation of a viral nucleocapsid protein DOI Creative Commons
Likai Ji,

Liying Zhou,

Ying Wang

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 18, 2024

Porcine deltacoronavirus (PDCoV), a newly discovered intestinal coronavirus, has rapidly spread among pigs worldwide and shown the potential for cross-species infection. However, interaction mechanism between PDCoV host’s antiviral response is still poorly understood. In this study, an E3 ubiquitin ligase FBXW8 was explored on proliferation. Our findings demonstrate that infection increases expression of through p65-mediated activation its promoter. We also suppresses replication by directly targeting inducing degradation PDCoV-encoded nucleocapsid (N) protein. Interestingly, catalyzes K48-linked polyubiquitination N protein at unique lysine-rich region (KR). Furthermore, we observed FBXW8-ubiquitinated interacts with NDP52, cargo receptor, leading to autophagic instead proteasomal degradation. summary, these reveal as novel host factor involved in It mediates NDP52-dependent These results provide new insights target defenses against PDCoV.

Language: Английский

Human MARCH1, 2, and 8 block Ebola virus envelope glycoprotein cleavage via targeting furin P domain DOI Creative Commons
Changqing Yu,

Yuanzhe Bai,

Wenbo Tan

et al.

Journal of Medical Virology, Journal Year: 2024, Volume and Issue: 96(2)

Published: Feb. 1, 2024

Abstract Membrane‐associated RING‐CH (MARCH) family proteins were recently reported to inhibit viral replication through multiple modes. Previous work showed that human MARCH8 blocked Ebola virus (EBOV) glycoprotein (GP) maturation. Our study here demonstrates MARCH1 and MARCH2 share a similar pattern in restricting EBOV GP‐pseudotyped infection. Human retain GP at the trans ‐Golgi network, reduce its cell surface display, impair virions infectivity. Furthermore, we uncover host proprotein convertase furin could interact with MARCH1/2 intracellularly. Importantly, P domain is verified be recognized by MARCH1/2/8, which critical for their blocking activities. Besides, bovine murine also proteolytic processing. Altogether, our findings confirm of different mammalian origins relatively conserved feature cleavage, provide clues subsequent MARCHs antiviral studies may facilitate development novel strategies antagonize enveloped

Language: Английский

Citations

13
Genetic risk factors for severe and fatigue dominant long COVID and commonalities with ME/CFS identified by combinatorial analysis DOI Creative Commons

Krystyna Taylor,

Matthew Pearson, Sayoni Das

et al.

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Nov. 1, 2023

Long COVID is a debilitating chronic condition that has affected over 100 million people globally. It characterized by diverse array of symptoms, including fatigue, cognitive dysfunction and respiratory problems. Studies have so far largely failed to identify genetic associations, the mechanisms behind disease, or any common pathophysiology with other conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present similar symptoms.We used combinatorial analysis approach combinations variants significantly associated development long examine biological underpinning its various symptoms. We compared two subpopulations patients from Sano Genetics' GOLD study cohort, focusing on severe dominant phenotypes. evaluated signatures previously identified in an ME/CFS population against this understand similarities disorders may be triggered prior viral infection. Finally, we also output known associations diseases, range metabolic neurological disorders, overlap pathophysiological mechanisms.Combinatorial 73 genes were highly at least one populations included analysis. Of these, 9 acute COVID-19, 14 differentially expressed transcriptomic patients. A pathway enrichment revealed pathways most mainly aligned cardiometabolic diseases. Expanded genotype suggests specific SNX9 genotypes are significant contributor risk protection infection, but gene-disease relationship context dependent mediated interactions KLF15 RYR3. Comparison uniquely Severe Fatigue Dominant differences between enriched each subgroup. The unique immune myeloid differentiation macrophage foam cells. Genes subgroup MAPK/JNK signaling. ME/CFS, several involved circadian rhythm regulation insulin regulation. Overall, 39 SNPs can linked recent patient UK Biobank. Among COVID, 42 potentially tractable for novel drug discovery approaches, 13 these already targeted drugs clinical pipelines. From example, TLR4 antagonists repurposing candidates potential protect term impairment pathology caused SARS-CoV-2. currently evaluating targets use treating and/or ME/CFS.This demonstrates power analytics stratifying heterogeneous complex diseases do not simple monogenic etiologies. These results build upon findings analyses COVID-19 expect access additional independent, larger datasets will further improve disease insights validate treatment options COVID.

Language: Английский

Citations

22
Host antiviral factors hijack furin to block SARS-CoV-2, ebola virus, and HIV-1 glycoproteins cleavage DOI Creative Commons
Changqing Yu, Guosheng Wang, Qiang Liu

et al.

Emerging Microbes & Infections, Journal Year: 2023, Volume and Issue: 12(1)

Published: Jan. 2, 2023

Viral envelope glycoproteins are crucial for viral infections. In the process of enveloped viruses budding and release from producer cells, presented on membrane surface as spikes, promoting virus's next-round infection target cells. However, host cells evolve counteracting mechanisms in long-term virus-host co-evolutionary processes. For instance, cell antiviral factors could potently suppress replication by targeting their through multiple channels, including intracellular synthesis, glycosylation modification, assembly into virions, binding to receptors. Recently, a group studies discovered that some proteins specifically recognized proprotein convertase (PC) furin blocked its cleavage glycoproteins, thus impairing infectivity. Here, this review, we briefly summarize several such analyze roles reducing aiming at providing insights future studies.

Language: Английский

Citations

20
The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer DOI Creative Commons
M. I. Khalil, Canchai Yang, Lexi Vu

et al.

Journal of Virology, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 16, 2024

ABSTRACT The human papillomavirus (HPV) oncoprotein E7 is a relatively short-lived protein required for HPV-driven cancer development and maintenance. degraded through ubiquitination mediated by cullin 1 (CUL1) the ubiquitin-conjugating enzyme E2 L3 (UBE2L3). However, proteins are maintained at high levels in most HPV-positive cells. A previous proteomics study has shown that UBE2L3 CUL1 increased knockdown of E3 ubiquitin ligase membrane-associated ring-CH-type finger 8 (MARCHF8). We have recently demonstrated HPV16 upregulates MARCHF8 expression keratinocytes head neck (HPV+ HNC) Here, we report stabilizes degrading components S-phase kinase-associated 1-CUL1-F-box complex HPV+ HNC found cells drastically decreases level while increasing levels. further revealed binds to ubiquitinates enhances protein. Conversely, overexpression suppresses tumor growth vivo . Our findings suggest HPV-induced prevents degradation ubiquitinating proteins. IMPORTANCE Since essential virus replication; HPV maintain HPV-infected can be efficiently ubiquitinated proteasomes host cell. Mechanistically, (UBE2L3) play an role degradation. show membrane (MARCHF8) induced E6 blocking proteasomes. knockout restores expression, decreasing inhibiting proliferation Additionally, or growth. results maintains cell inducing MARCHF8, which may critical tumorigenesis.

Language: Английский

Citations

7
EGR1 functions as a new host restriction factor for SARS-CoV-2 to inhibit virus replication through the E3 ubiquitin ligase MARCH8 DOI
Y. Zhao,

Liyan Sui,

Ping Wu

et al.

Journal of Virology, Journal Year: 2023, Volume and Issue: 97(10)

Published: Sept. 29, 2023

Emerging vaccine-breakthrough severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight an urgent need for novel antiviral therapies. Understanding the pathogenesis of coronaviruses is critical developing drugs. Here, we demonstrate that SARS-CoV-2 N protein suppresses interferon (IFN) responses by reducing early growth response gene-1 (EGR1) expression. The overexpression EGR1 inhibits replication promoting IFN-regulated expression, which interacts with and degrades via E3 ubiquitin ligase MARCH8 cargo receptor NDP52. mutants without activity are no longer able to degrade proteins, indicating proteins dependent on its activity. This study found a immune evasion mechanism utilized protein, helpful understanding guiding design new prevention strategies against emerging coronaviruses.

Language: Английский

Citations

16
Restriction of Viral Glycoprotein Maturation by Cellular Protease Inhibitors DOI Creative Commons
Rishikesh Lotke,

Moritz Petersen,

Daniel Sauter

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(3), P. 332 - 332

Published: Feb. 22, 2024

The human genome is estimated to encode more than 500 proteases performing a wide range of important physiological functions. They digest proteins in our food, determine the activity hormones, induce cell death and regulate blood clotting, for example. During viral infection, however, some can switch sides activate glycoproteins, allowing entry virions into new target cells spread infection. To reduce unwanted effects, multiple protease inhibitors proteolytic processing self non-self proteins. This review summarizes current knowledge endogenous inhibitors, which are known limit replication by interfering with activation glycoproteins. We describe underlying molecular mechanisms highlight diverse strategies virion infectivity. also provide examples how viruses evade restriction imposed inhibitors. Finally, we briefly outline cellular be modified exploited therapeutic purposes. In summary, this aims summarize understanding as components immune response variety pathogens.

Language: Английский

Citations

6
Ubiquitin Ligase Parkin Regulates the Stability of SARS-CoV-2 Main Protease and Suppresses Viral Replication DOI Creative Commons
Li Zhou, Ruochuan Liu,

Heather Pathak

et al.

ACS Infectious Diseases, Journal Year: 2024, Volume and Issue: 10(3), P. 879 - 889

Published: Feb. 22, 2024

The highly infectious coronavirus SARS-CoV-2 relies on the viral main protease (Mpro, also known as 3CLpro or Nsp5) to proteolytically process polyproteins encoded by genome for release of functional units in host cells initiate replication. Mpro interacts with proteins innate immune pathways, such IRF3 and STAT1, suppress their activities facilitate virus survival proliferation. To identify mechanism regulating Mpro, we screened various classes E3 ubiquitin ligases found that Parkin RING-between-RING family can induce ubiquitination degradation cell. Furthermore, when undergo mitophagy, PINK1 kinase activates enhances Mpro. We elevated expression significantly decreased replication virus. Interestingly, infection downregulates mouse lung tissues compared healthy controls. These results suggest an antiviral role a ligase targeting potential exploiting virus–host interaction mediated treat infection.

Language: Английский

Citations

5
The emerging roles of MARCH8 in viral infections: A double-edged Sword DOI Creative Commons
Changqing Yu, Qiang Liu, Zhuo Zhao

et al.

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(9), P. e1011619 - e1011619

Published: Sept. 14, 2023

The host cell membrane-associated RING-CH 8 protein (MARCH8), a member of the E3 ubiquitin ligase family, regulates intracellular turnover many transmembrane proteins and shows potent antiviral activities. Generally, 2 modes are performed by MARCH8. On one hand, MARCH8 catalyzes viral envelope glycoproteins (VEGs) ubiquitination thus leads to their degradation, which is cytoplasmic tail (CT)-dependent (CTD) mode. other traps VEGs at some compartments (such as trans-Golgi network, TGN) but without inducing tail-independent (CTI) mode, hijacks furin, cellular proprotein convertase, block cleavage. In addition, C-terminal tyrosine-based motif (TBM) 222YxxL225 also plays key role in its CTI effects. contrast potency, occasionally hijacked viruses bacteria enhance invasion, indicating duplex pathogenic infections. This review summarizes MARCH8's roles how evade restriction, shedding light on novel therapeutic avenues.

Language: Английский

Citations

12
Modulation of Lymphotoxin β Surface Expression by Kaposi's Sarcoma‐Associated Herpesvirus K3 Through Glycosylation Interference DOI Creative Commons
Soowon Kang, Kevin Brulois, Youn Jung Choi

et al.

Journal of Medical Virology, Journal Year: 2025, Volume and Issue: 97(1)

Published: Jan. 1, 2025

ABSTRACT Kaposi's sarcoma‐associated herpesvirus (KSHV) employs diverse mechanisms to subvert host immune responses, contributing its infection and pathogenicity. As an evasion strategy, KSHV encodes the Membrane‐Associated RING‐CH (MARCH)‐family E3 ligases, K3, K5, which target remove several regulators from cell surface. In this study, we investigate impact of K3 K5 on lymphotoxin receptor (LTβR) ligands, LTβ LIGHT, are type II transmembrane proteins function as pivotal mediators during virus infection. Upon co‐expression viral MARCH with LTβR showed that selectively targeted LTβ, but not for downregulation surface expression. Specifically, ligases interacted domain LTβ. Intriguingly, immature form whereas fully mature form. Subsequent biochemical analyses revealed disrupted initial steps N‐glycosylation maturation This interference resulted in sequestration within endoplasmic reticulum, impeding trafficking plasma membrane. Consequently, K3‐mediated expression suppressed downstream signaling pathway. These findings uncover a novel mechanism by ligase inhibits membrane pathway inflammatory ligand through glycosylation interference, potentially evading LTβR‐mediated antiviral immunity.

Language: Английский

Citations

0
Regulation of viral replication by host restriction factors DOI Creative Commons
Ying Lin, Yun Zhu, Ling Jing

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 23, 2025

Viral infectious diseases, caused by numerous viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus (IAV), enterovirus (EV), human immunodeficiency (HIV), hepatitis B (HBV), and papillomavirus (HPV), pose a continuous threat to global health. As obligate parasites, rely on host cells replicate, have developed defense mechanisms counteract viral infection. Host restriction factors (HRFs) are critical components of the early antiviral response. These cellular proteins inhibit replication spread impeding essential steps in life cycle, such as entry, genome transcription replication, protein translation, particle assembly, release. This review summarizes current understanding how with primary focus their diverse against range viruses, SARS-CoV-2, virus, enteroviruses, papillomavirus. In addition, we highlight crucial role these shaping host-virus interactions discuss potential targets for drug development.

Language: Английский

Citations

0