Flavivirus NS2A orchestrates reticulophagy to enhance viral pathogenicity

Autophagy, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 2

Published: Feb. 4, 2025

Selective endoplasmic reticulum (ER) autophagy (reticulophagy) is essential for maintaining ER homeostasis. The E3 ligase AMFR facilitates the ubiquitination of reticulophagy receptor RETREG1/FAM134B, thereby promoting dynamic flux process. Flaviviruses exploit during their replication cycles, highlighting importance quantity and accessibility in flavivirus infections. However, role viral complex mechanisms by which viruses modulate to enhance pathogenicity remain poorly understood. In a recent study, we demonstrate that Zika virus (ZIKV) hijacks ER-located ubiquitinate NS2A, leading degradation key RETREG1. This inhibition process promotes virus-induced microcephaly human brain organoids enhances mouse models. Notably, AMFR-mediated ZIKV-NS2A its functional interaction with RETREG1 are conserved across NS2A other flaviviruses, including those from Dengue virus, West Nile Japanese encephalitis virus.

Language: Английский

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Functional Roles and Host Interactions of Orthoflavivirus Non-Structural Proteins During Replication

Pathogens, Journal Year: 2025, Volume and Issue: 14(2), P. 184 - 184

Published: Feb. 12, 2025

Orthoflavivirus, a genus encompassing arthropod-borne, positive-sense, single-stranded RNA viruses in the Flaviviridae family, represents clinically relevant that pose significant threats to human and animal health worldwide. With warming climates persistent urbanization, arthropod vectors they transmit continue widen their geographic distribution, expanding endemic zones. Flaviviruses such as dengue virus, Zika West Nile tick-borne encephalitis virus cause debilitating fatal infections globally. In 2024, World Health Organization Pan American declared current situation Multi-Country Grade 3 Outbreak, highest level. FDA-approved treatment options for diseases caused by flaviviruses are limited or non-existent, vaccines suboptimal many flaviviruses. Understanding molecular characteristics of flavivirus life cycle, virus-host interactions, resulting pathogenesis various cells model systems is critical developing effective therapeutic intervention strategies. This review will focus on interactions mosquito- from replication assembly perspective, emphasizing interplay between viral non-structural proteins host pathways hijacked advantage. Highlighting interaction pathways, including innate immunity, intracellular movement, membrane modification, emphasizes need rigorous targeted antiviral research development against these re-emerging viruses.

Language: Английский

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E3 ubiquitin ligase MARCH5 positively regulates Japanese encephalitis virus infection by catalyzing the K27-linked polyubiquitination of viral E protein and inhibiting MAVS-mediated type I interferon production

mBio, Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

ABSTRACT Membrane-associated RING-CH-type finger (MARCH) proteins, a class of E3 ubiquitin ligases, have been reported to be involved in the infection multiple viruses and regulation type I interferon (IFN) production. However, specific role mechanisms by which MARCH proteins influence Japanese encephalitis virus (JEV) remain poorly understood. Here, we systematically investigate functional relevance JEV replication examining effects siRNA-mediated knockdown MARCHs on viral infection. We identified MARCH5 as positive regulator replication. The knockout dramatically reduced yields, whereas its overexpression significantly enhanced Mechanistically, specifically interacts with envelope (E) protein promotes K27-linked polyubiquitination at lysine (K) residues 136 166. This ubiquitination enhances attachment permissive cells. Substituting these arginine (R) attenuated vitro virulence vivo . Furthermore, upregulated expression MARCH5. also discovered that degrades mitochondrial antiviral-signaling (MAVS) through ubiquitin-proteasome pathway catalyzing K48-linked ubiquitination, thereby inhibiting IFN production JEV-infected suppression further facilitates In conclusion, findings disclosed novel positively regulating revealed an important mechanism employed regulate innate immune response. IMPORTANCE is leading cause many countries Asia estimated 100,000 clinical human cases causes economic loss swine industry. Until now, there no clinically approved antiviral for treatment Although vaccination prophylaxis widely regarded most effective strategy preventing (JE), incidence JE continues rise. Thus, deeper understanding virus-host interaction will enrich our knowledge underlying identify targets development next-generation live-attenuated vaccines therapies. To best knowledge, this study first pro-viral host factor elucidated two distinct First, E mediates K136 K166 facilitate efficient attachment. double mutations K136R-K166R mice. Second, induced suppresses RIG-I-like receptor (RLR) signaling benefit downregulates conjugating polyubiquitin K286 MAVS, leads MAVS degradation pathway. summary, provides insights into played identifies sites could targeted attenuation therapeutics.

Language: Английский

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The ER-phagy receptor FAM134B is targeted by Salmonella Typhimurium to promote infection

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 25, 2025

Macroautophagy/autophagy is a key catabolic-recycling pathway that can selectively target damaged organelles or invading pathogens for degradation. The selective autophagic degradation of the endoplasmic reticulum (hereafter referred to as ER-phagy) homeostatic mechanism, controlling ER size, removal misfolded protein aggregates, and organelle damage. ER-phagy also be stimulated by pathogen infection. However, link between bacterial infection remains poorly understood, are mechanisms evolved escape effects ER-phagy. Here, we show Salmonella enterica serovar Typhimurium inhibits targeting receptor FAM134B, leading pronounced increase in burden after invasion. prevents FAM134B oligomerization, which required efficient knock-out raises intracellular number, while activation reduces burden. Additionally, found targets through effector SopF enhance survival inhibition. Furthermore, mice infected with presented severe intestinal damage increased These results provide mechanistic insight into interplay infection, highlighting role innate immunity. Gatica et al resides reticulum, targeted limited Typhimurium. This restriction autophagy enhances within host cells.

Language: Английский

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