Dengue virion releases its genome

Stable Identifier
R-HSA-9922491
Type
Reaction [uncertain]
Species
Homo sapiens
Related Species
Dengue virus type 2
Compartment
cytosol, endosome membrane
ReviewStatus
5/5
Locations in the PathwayBrowser
Expand all
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
Dengue virion releases its genome
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
The majority of DENV particles are transported from early endosomes to late endosomes. Low pH in the late endosome triggers the dissociation of the E dimer, insertion of the fusion loop into the endosome membrane, and refolding to a trimeric E hairpin to drive uncoating, releasing the viral genome in the host cell cytosol (van der Schaar et al., 2007; Zheng et al., 2014). A subset of the virions are immature, in that prM was not fully cleaved during virion assembly. For virions without any cleaved prM subunits, infectivity often depends on antibody-mediated entry followed by furin cleavage in endosomes or on the cell surface. Partially mature virions can be infectious due to their already processed E proteins, though further processing of remaining prM may occur post-entry (reviewed in Rodenhuis-Zybert et al., 2011; Smit et al., 2011; Cruz-Oliveira et al., 2015).

In studies using A549 (human lung carcinoma) and BHK-21 (baby hamster kidney) cells infected with DENV-2 (strain 16681), genome uncoating was inhibited when ubiquitin E1 activity is blocked. The mechanism of this regulation is unclear (Byk et al., 2016). In studies using HEK 293T (human embryonic kidney) and Huh 7.5.1 (human hepatoma) cells infected with a DENV-2 reporter virus (derived from strain 16681), membrane fusion was found to require an influx of phosphatidylserine (PS) from the ER membrane, mediated by ER membrane protein complex subunit 4 (EMC4) (Bagchi et al., 2022).

Chloroquine is a drug approved for malaria. It inhibits Dengue replication in vitro in several mammalian cell lines (e.g., Vero, U937), probably by increasing pH in endosomes and other organelles, though this effect was not observed in A. albopictus C6/36 mosquito cells (reviewed in Kaptein & Neyts, 2016; Wei & Jiang, 2020; Tricou et al., 2010). A clinical trial with chloroquine in adult dengue patients did not show a reduction in the primary virological endpoints of viraemia or NS1 antigenaemia, though it was associated with a significant reduction in fever clearance time in the intention-to-treat population and a trend towards a lower incidence of dengue hemorrhagic fever (Tricou et al., 2010; reviewed in Kaptein & Neyts, 2016).

Niclosamide is an approved anthelminthic and causes endosomal deacidification, suppressing virion membrane fusion on entry and virion maturation on release (Kao et al., 2018).
Literature References
PubMed ID Title Journal Year
24846574 A toggle switch controls the low pH-triggered rearrangement and maturation of the dengue virus envelope proteins

Zheng, A, Yuan, F, Kleinfelter, LM, Kielian, M

Nat Commun 2014
20706626 A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults

Tricou, V, Minh, NN, Van, TP, Lee, SJ, Farrar, J, Wills, B, Tran, HT, Simmons, CP

PLoS Negl Trop Dis 2010
30125275 The antiparasitic drug niclosamide inhibits dengue virus infection by interfering with endosomal acidification independent of mTOR

Kao, JC, HuangFu, WC, Tsai, TT, Ho, MR, Jhan, MK, Shen, TJ, Tseng, PC, Wang, YT, Lin, CF

PLoS Negl Trop Dis 2018
17728239 Characterization of the early events in dengue virus cell entry by biochemical assays and single-virus tracking

van der Schaar, HM, Rust, MJ, Waarts, BL, van der Ende-Metselaar, H, Kuhn, RJ, Wilschut, J, Zhuang, X, Smit, JM

J Virol 2007
35834589 A specific EMC subunit supports Dengue virus infection by promoting virus membrane fusion essential for cytosolic genome delivery

Bagchi, P, Speckhart, K, Kennedy, A, Tai, AW, Tsai, B

PLoS Pathog 2022
21388812 Partial maturation: an immune-evasion strategy of dengue virus?

Rodenhuis-Zybert, IA, Wilschut, J, Smit, JM

Trends Microbiol 2011
32633413 The antiviral mechanisms, effects, safety and adverse effects of chloroquine

Wei, ZX, Tang, TT, Jiang, SP

Eur Rev Med Pharmacol Sci 2020
27367615 Towards antiviral therapies for treating dengue virus infections

Kaptein, SJ, Neyts, J

Curr Opin Pharmacol 2016
22049308 Flavivirus cell entry and membrane fusion

Smit, JM, Moesker, B, Rodenhuis-Zybert, I, Wilschut, J

Viruses 2011
27353759 Dengue Virus Genome Uncoating Requires Ubiquitination

Byk, LA, Iglesias, NG, De Maio, FA, Gebhard, LG, Rossi, M, Gamarnik, AV

mBio 2016
25725010 Receptors and routes of dengue virus entry into the host cells

Cruz-Oliveira, C, Freire, JM, Conceição, TM, Higa, LM, Castanho, MA, Da Poian, AT

FEMS Microbiol Rev 2015
Participants
Input
Output
Participates
as an event of
Event Information
Go Biological Process
fusion of virus membrane with host endosome membrane (0039654)
This event is regulated
Negatively by
Regulator
CQ2+ [endocytic vesicle lumen]
Regulator
niclosamide [endosome lumen]
Positively by
Regulator
FURIN [endosome membrane] (Homo sapiens)
Requirements
Disease
Name Identifier Synonyms
dengue disease DOID:12205 breakbone fever, Dengue Fever, classic dengue
Cross References
Mondo
Authored
Stephan, R  (2024-10-07)
Reviewed
Mansur, DS  (2025-10-29)
Roque Ascenção, F  (2025-10-29)
Created
Stephan, R  (2024-09-24)
Cite Us!