Enhanced SARS-CoV-2 entry via UPR-dependent AMPK-related kinase NUAK2

Vibhu Prasad; B Cerikan; Yannick Stahl; K Kopp; V Magg; N Acosta-Rivero; H Kim; K Klein; C Funaya; U Haselmann; M Cortese; F Heigwer; Josephine Bageritz; D Bitto; S Jargalsaikhan; C Neufeldt; Felix Pahmeier; M Boutros; Y Yamauchi; A Ruggieri; R Bartenschlager

doi:10.1016/j.molcel.2023.06.020

Enhanced SARS-CoV-2 entry via UPR-dependent AMPK-related kinase NUAK2

Vibhu Prasad^*, B Cerikan, Yannick Stahl, K Kopp, V Magg, N Acosta-Rivero, H Kim, K Klein, C Funaya, U Haselmann, M Cortese, F Heigwer, Josephine Bageritz, D Bitto, S Jargalsaikhan, C Neufeldt, Felix Pahmeier, M Boutros, Y Yamauchi, A RuggieriR Bartenschlager^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

17 Citations (Scopus)

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remodels the endoplasmic reticulum (ER) to form replication organelles, leading to ER stress and unfolded protein response (UPR). However, the role of specific UPR pathways in infection remains unclear. Here, we found that SARS-CoV-2 infection causes marginal activation of signaling sensor IRE1α leading to its phosphorylation, clustering in the form of dense ER-membrane rearrangements with embedded membrane openings, and XBP1 splicing. By investigating the factors regulated by IRE1α-XBP1 during SARS-CoV-2 infection, we identified stress-activated kinase NUAK2 as a novel host-dependency factor for SARS-CoV-2, HCoV-229E, and MERS-CoV entry. Reducing NUAK2 abundance or kinase activity impaired SARS-CoV-2 particle binding and internalization by decreasing cell surface levels of viral receptors and viral trafficking likely by modulating the actin cytoskeleton. IRE1α-dependent NUAK2 levels were elevated in SARS-CoV-2-infected and bystander non-infected cells, promoting viral spread by maintaining ACE2 cell surface levels and facilitating virion binding to bystander cells.

Original language	English
Pages (from-to)	2559–2577.e8
Number of pages	27
Journal	Molecular Cell
Volume	83
Issue number	14
DOIs	https://doi.org/10.1016/j.molcel.2023.06.020
Publication status	Published - 7 Jul 2023

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Prasad, V., Cerikan, B., Stahl, Y., Kopp, K., Magg, V., Acosta-Rivero, N., Kim, H., Klein, K., Funaya, C., Haselmann, U., Cortese, M., Heigwer, F., Bageritz, J., Bitto, D., Jargalsaikhan, S., Neufeldt, C., Pahmeier, F., Boutros, M., Yamauchi, Y., ... Bartenschlager, R. (2023). Enhanced SARS-CoV-2 entry via UPR-dependent AMPK-related kinase NUAK2. Molecular Cell, 83(14), 2559–2577.e8. https://doi.org/10.1016/j.molcel.2023.06.020

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title = "Enhanced SARS-CoV-2 entry via UPR-dependent AMPK-related kinase NUAK2",

abstract = "Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remodels the endoplasmic reticulum (ER) to form replication organelles, leading to ER stress and unfolded protein response (UPR). However, the role of specific UPR pathways in infection remains unclear. Here, we found that SARS-CoV-2 infection causes marginal activation of signaling sensor IRE1α leading to its phosphorylation, clustering in the form of dense ER-membrane rearrangements with embedded membrane openings, and XBP1 splicing. By investigating the factors regulated by IRE1α-XBP1 during SARS-CoV-2 infection, we identified stress-activated kinase NUAK2 as a novel host-dependency factor for SARS-CoV-2, HCoV-229E, and MERS-CoV entry. Reducing NUAK2 abundance or kinase activity impaired SARS-CoV-2 particle binding and internalization by decreasing cell surface levels of viral receptors and viral trafficking likely by modulating the actin cytoskeleton. IRE1α-dependent NUAK2 levels were elevated in SARS-CoV-2-infected and bystander non-infected cells, promoting viral spread by maintaining ACE2 cell surface levels and facilitating virion binding to bystander cells.",

author = "Vibhu Prasad and B Cerikan and Yannick Stahl and K Kopp and V Magg and N Acosta-Rivero and H Kim and K Klein and C Funaya and U Haselmann and M Cortese and F Heigwer and Josephine Bageritz and D Bitto and S Jargalsaikhan and C Neufeldt and Felix Pahmeier and M Boutros and Y Yamauchi and A Ruggieri and R Bartenschlager",

year = "2023",

month = jul,

day = "7",

doi = "10.1016/j.molcel.2023.06.020",

language = "English",

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journal = "Molecular Cell",

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Prasad, V, Cerikan, B, Stahl, Y, Kopp, K, Magg, V, Acosta-Rivero, N, Kim, H, Klein, K, Funaya, C, Haselmann, U, Cortese, M, Heigwer, F, Bageritz, J, Bitto, D, Jargalsaikhan, S, Neufeldt, C, Pahmeier, F, Boutros, M, Yamauchi, Y, Ruggieri, A & Bartenschlager, R 2023, 'Enhanced SARS-CoV-2 entry via UPR-dependent AMPK-related kinase NUAK2', Molecular Cell, vol. 83, no. 14, pp. 2559–2577.e8. https://doi.org/10.1016/j.molcel.2023.06.020

TY - JOUR

T1 - Enhanced SARS-CoV-2 entry via UPR-dependent AMPK-related kinase NUAK2

AU - Prasad, Vibhu

AU - Cerikan, B

AU - Stahl, Yannick

AU - Kopp, K

AU - Magg, V

AU - Acosta-Rivero, N

AU - Kim, H

AU - Klein, K

AU - Funaya, C

AU - Haselmann, U

AU - Cortese, M

AU - Heigwer, F

AU - Bageritz, Josephine

AU - Bitto, D

AU - Jargalsaikhan, S

AU - Neufeldt, C

AU - Pahmeier, Felix

AU - Boutros, M

AU - Yamauchi, Y

AU - Ruggieri, A

AU - Bartenschlager, R

PY - 2023/7/7

Y1 - 2023/7/7

N2 - Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remodels the endoplasmic reticulum (ER) to form replication organelles, leading to ER stress and unfolded protein response (UPR). However, the role of specific UPR pathways in infection remains unclear. Here, we found that SARS-CoV-2 infection causes marginal activation of signaling sensor IRE1α leading to its phosphorylation, clustering in the form of dense ER-membrane rearrangements with embedded membrane openings, and XBP1 splicing. By investigating the factors regulated by IRE1α-XBP1 during SARS-CoV-2 infection, we identified stress-activated kinase NUAK2 as a novel host-dependency factor for SARS-CoV-2, HCoV-229E, and MERS-CoV entry. Reducing NUAK2 abundance or kinase activity impaired SARS-CoV-2 particle binding and internalization by decreasing cell surface levels of viral receptors and viral trafficking likely by modulating the actin cytoskeleton. IRE1α-dependent NUAK2 levels were elevated in SARS-CoV-2-infected and bystander non-infected cells, promoting viral spread by maintaining ACE2 cell surface levels and facilitating virion binding to bystander cells.

AB - Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remodels the endoplasmic reticulum (ER) to form replication organelles, leading to ER stress and unfolded protein response (UPR). However, the role of specific UPR pathways in infection remains unclear. Here, we found that SARS-CoV-2 infection causes marginal activation of signaling sensor IRE1α leading to its phosphorylation, clustering in the form of dense ER-membrane rearrangements with embedded membrane openings, and XBP1 splicing. By investigating the factors regulated by IRE1α-XBP1 during SARS-CoV-2 infection, we identified stress-activated kinase NUAK2 as a novel host-dependency factor for SARS-CoV-2, HCoV-229E, and MERS-CoV entry. Reducing NUAK2 abundance or kinase activity impaired SARS-CoV-2 particle binding and internalization by decreasing cell surface levels of viral receptors and viral trafficking likely by modulating the actin cytoskeleton. IRE1α-dependent NUAK2 levels were elevated in SARS-CoV-2-infected and bystander non-infected cells, promoting viral spread by maintaining ACE2 cell surface levels and facilitating virion binding to bystander cells.

U2 - 10.1016/j.molcel.2023.06.020

DO - 10.1016/j.molcel.2023.06.020

M3 - Article (Academic Journal)

C2 - 37421942

SN - 1097-2765

VL - 83

SP - 2559–2577.e8

JO - Molecular Cell

JF - Molecular Cell

IS - 14

ER -

Enhanced SARS-CoV-2 entry via UPR-dependent AMPK-related kinase NUAK2

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