The uncoating of EV71 in mature late endosomes requires CD-M6PR

Ohka, Seii; Tan, Soon Hao; Ishiyama, Eri; Ogasawara, Katsutoshi; Hanasaka, Tomohito; Ishida, Katsuaki; Hagiwara, Kyoji; Liu, Chia-Chyi; Chong, Pele; Hanaki, Ken-Ichi; Schiavo, Giampietro

doi:10.1242/bio.059469

Cited by 9 publications

(6 citation statements)

References 42 publications

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“…S8). In addition, it was reported that RAB11AS25N localised at the trans-Golgi network (TGN) forming a dense perinuclear staining pattern [ 24 , 41 , 44 ], and this was also observed in our experiment (Suppl. Fig.…”

Section: Resultssupporting

confidence: 87%

Enterovirus-A71 exploits RAB11 to recruit chaperones for virus morphogenesis

Ng,

Mahendran,

Lim

et al. 2024

J Biomed Sci

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Background Enterovirus 71 (EV-A71) causes Hand, Foot and Mouth Disease (HFMD) in children and has been associated with neurological complications. The molecular mechanisms involved in EV-A71 pathogenesis have remained elusive. Methods A siRNA screen in EV-A71 infected-motor neurons was performed targeting 112 genes involved in intracellular membrane trafficking, followed by validation of the top four hits using deconvoluted siRNA. Downstream approaches including viral entry by-pass, intracellular viral genome quantification by qPCR, Western blot analyses, and Luciferase reporter assays allowed determine the stage of the infection cycle the top candidate, RAB11A was involved in. Proximity ligation assay, co-immunoprecipitation and multiplex confocal imaging were employed to study interactions between viral components and RAB11A. Dominant negative and constitutively active RAB11A constructs were used to determine the importance of the protein’s GTPase activity during EV-A71 infection. Mass spectrometry and protein interaction analyses were employed for the identification of RAB11A’s host interacting partners during infection. Results Small GTPase RAB11A was identified as a novel pro-viral host factor during EV-A71 infection. RAB11A and RAB11B isoforms were interchangeably exploited by strains from major EV-A71 genogroups and by Coxsackievirus A16, another major causative agent of HFMD. We showed that RAB11A was not involved in viral entry, IRES-mediated protein translation, viral genome replication, and virus exit. RAB11A co-localized with replication organelles where it interacted with structural and non-structural viral components. Over-expression of dominant negative (S25N; GDP-bound) and constitutively active (Q70L; GTP-bound) RAB11A mutants had no effect on EV-A71 infection outcome, ruling out RAB11A’s involvement in intracellular trafficking of viral or host components. Instead, decreased ratio of intracellular mature viral particles to viral RNA copies and increased VP0:VP2 ratio in siRAB11-treated cells supported a role in provirion maturation hallmarked by VP0 cleavage into VP2 and VP4. Finally, chaperones, not trafficking and transporter proteins, were found to be RAB11A’s top interacting partners during EV-A71 infection. Among which, CCT8 subunit from the chaperone complex TRiC/CCT was further validated and shown to interact with viral structural proteins specifically, representing yet another novel pro-viral host factor during EV-A71 infection. Conclusions This study describes a novel, unconventional role for RAB11A during viral infection where it participates in the complex process of virus morphogenesis by recruiting essential chaperone proteins.

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Section: Resultssupporting

confidence: 87%

Enterovirus-A71 exploits RAB11 to recruit chaperones for virus morphogenesis

Ng,

Mahendran,

Lim

et al. 2024

J Biomed Sci

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“…The selection of a specific receptor varies among distinct viruses or different subtypes of the same virus. These viruses encompass Herpesviridae (HSV - 1, HSV - 2), varicella zoster virus (VZV) and human immunodeficiency virus 1 (HIV-1) among others ( Figure 2 ) ( Brunetti et al., 1994 ; Mbemba et al., 1994 ; Brunetti et al., 1995 ; Chen et al., 2004 ; Dohgu et al., 2012 ; Díaz-Salinas et al., 2018 ; Ohka et al., 2022 ). Table 1 enumerates the specific surface glycoprotein ligands for each virus and their corresponding host M6PR entry receptors ( Table 1 ).…”

Section: M6p Pathway and Viral Infectionmentioning

confidence: 99%

“…Enterovirus 71 (EV71), responsible for causing hand-foot-mouth disease, relies on CI-MPR present on the host cell surface as a co-receptor along with scavenger receptor B2 (SCARB2) to facilitate its entry into the cell. Once the virus is internalized, it is directed to the late endosome for uncoating, a process in which CD-MPR is essential ( Ohka et al., 2022 ). However, the precise role of CD-MPR in either transporting EV71 particles into the late endosome or delivering cathepsins to the late endosome to facilitate the final uncoating phase has yet to be investigated.…”

Section: M6p Pathway and Viral Infectionmentioning

confidence: 99%

The host mannose-6-phosphate pathway and viral infection

Liu,

Wang,

et al. 2024

Front. Cell. Infect. Microbiol.

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Viruses, despite their simple structural composition, engage in intricate and complex interactions with their hosts due to their parasitic nature. A notable demonstration of viral behavior lies in their exploitation of lysosomes, specialized organelles responsible for the breakdown of biomolecules and clearance of foreign substances, to bolster their own replication. The man-nose-6-phosphate (M6P) pathway, crucial for facilitating the proper transport of hydrolases into lysosomes and promoting lysosome maturation, is frequently exploited for viral manipulation in support of replication. Recently, the discovery of lysosomal enzyme trafficking factor (LYSET) as a pivotal regulator within the lysosomal M6P pathway has introduced a fresh perspective on the intricate interplay between viral entry and host factors. This groundbreaking revelation illuminates unexplored dimensions of these interactions. In this review, we endeavor to provide a thorough overview of the M6P pathway and its intricate interplay with viral factors during infection. By consolidating the current understanding in this field, our objective is to establish a valuable reference for the development of antiviral drugs that selectively target the M6P pathway.

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“…Mature virions attach to cells via cell surface receptors/co-receptors and the genome is released following conformational changes induced by receptor interaction and/or local environmental changes (pH and ionic changes in endosomes etc.) [1][2][3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Mechanism of enterovirus VP0 maturation cleavage based on the structure of a stabilised assembly intermediate

Kingston,

Snowden,

Grehan

et al. 2024

Preprint

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Molecular details of genome packaging are little understood for the majority of viruses. In enteroviruses (EVs), cleavage of the structural protein VP0 into VP4 and VP2 is initiated by the incorporation of RNA into the assembling virion and is essential for infectivity. We have applied a combination of bioinformatic, molecular and structural approaches to generate the first high-resolution structure of an intermediate in the assembly pathway, termed a provirion, which contains RNA and intact VP0. We have demonstrated an essential role of VP0 E096 in VP0 cleavage independent of RNA encapsidation and generated a new model of capsid maturation, supported by bioinformatic analysis. This provides a molecular basis for RNA-dependence, where RNA induces conformational changes required for VP0 maturation, but that RNA packaging itself is not sufficient to induce maturation. These data have implications for understanding production of infectious virions and potential relevance for future vaccine and antiviral drug design.

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The uncoating of EV71 in mature late endosomes requires CD-M6PR

Cited by 9 publications

References 42 publications

Enterovirus-A71 exploits RAB11 to recruit chaperones for virus morphogenesis

Enterovirus-A71 exploits RAB11 to recruit chaperones for virus morphogenesis

The host mannose-6-phosphate pathway and viral infection

Mechanism of enterovirus VP0 maturation cleavage based on the structure of a stabilised assembly intermediate

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