SARS-CoV-2 3a tetramer binds to VPS39 within HOPS complex

Stable Identifier
R-HSA-9754537
Type
Reaction [binding]
Species
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
Compartment
endolysosome membrane, endosome membrane
ReviewStatus
5/5
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SARS-CoV-2 3a tetramer binds to VPS39 within HOPS complex
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SARS-CoV-2 viroporin 3a (ORF3a) is a membrane protein that translocates to the cellular membranes. Coexpression of viral 3a with markers for endolysosomal compartments in HeLa revealed that 3a also localizes to the late endosome and/or lysosome. On late endosomes/lysosomes, viral 3a inhibits autophagosomal flux (Miao G et al. 2021; Zhang Y et al. 2021). In in vitro GST-pull-down assays, viral 3a directly interacted with VPS39, a component of the homotypic fusion and protein sorting (HOPS) complex (Miao G et al. 2021). Moreover, the viral 3a protein co-immunoprecipitated with VPS39 upon co-expression of the tagged proteins in human embryonic kidney 293T (HEK293T) and cervical cancer HeLa cells (Miao G et al. 2021; Zhang Y et al. 2021). Affinity purification using HEK 293T/17 cells coupled with mass spectrometry (AP-MS) analysis further confirmed the interaction between viral 3a and VPS39 (Gordon DE et al. 2020). In human cells, the binding of 3a to VPS39 blocked the interaction of the HOPS complex with autophagosomal STX17, which is essential for autophagosome-lysosome fusion (Miao G et al. 2021). Further, SARS-CoV-2 3a expression in HEK293T resulted in the accumulation of the autophagy-associated factor MAP1LC3B (Stukalov A et al. 2021). The impact of 3a on autophagosomal flux was further confirmed by the pathway-enrichment analysis which showed that the 3a-mediated inhibition of autophagic flux leads to the accumulation of autophagy receptors (SQSTM1, GABARAPL2, NBR1, CALCOCO2, MAP1LC3A, MAP1LC3B and TAX1BP1) (Stukalov A et al. 2021). Although 3a proteins are highly conserved between the SARS-CoV-1 and SARS-CoV-2 coronaviruses, SARS-CoV-1 3a was found to be unable to interact with the HOPS complex and showed no effect on autophagy response (Miao G et al. 2021).

This Reactome event describes the interaction of SARS-CoV-2 3a (ORF3a) with human VPS39 within the HOPS complex. This interaction prevents the autophagosome-lysosome fusion.

Literature References
PubMed ID Title Journal Year
33422265 ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation

Zhang, H, Ji, M, Li, Y, Miao, G, Shi, Y, Bi, Y, Zhao, H, Chen, Y, Wang, P

Dev Cell 2021
33947832 The SARS-CoV-2 protein ORF3a inhibits fusion of autophagosomes with lysosomes

Zhang, Y, Pei, R, Lin, Y, Mao, B, Sun, H, Lu, K, Zhao, Z, Li, H

Cell Discov 2021
Participants
Input
Output
Participates
as an event of
Disease
Name Identifier Synonyms
COVID-19 DOID:0080600 2019 Novel Coronavirus (2019-nCoV), Wuhan seafood market pneumonia virus infection, 2019-nCoV infection, Wuhan coronavirus infection
Authored
Shamovsky, V  (2021-10-27)
Reviewed
Messina, F  (2022-02-18)
Created
Shamovsky, V  (2021-09-28)
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