SAMHD1 depletion restricts SARS-CoV-2 infection by suppressing HNF1-dependent ACE2 expression in lung epithelial cells

Pak-Hin Hinson Cheung; Pearl Chan; Hua Yang; Krisztina Ambrus; Shravya Honne; Baek Kim; Stanley Perlman; Li Wu

doi:10.1371/journal.ppat.1013659

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SAMHD1 depletion restricts SARS-CoV-2 infection by suppressing HNF1-dependent ACE2 expression in lung epithelial cells

Journal article

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SAMHD1 depletion restricts SARS-CoV-2 infection by suppressing HNF1-dependent ACE2 expression in lung epithelial cells

Pak-Hin Hinson Cheung, Pearl Chan, Hua Yang, Krisztina Ambrus, Shravya Honne, Baek Kim, Stanley Perlman and Li Wu

PLoS pathogens, Vol.22(3), e1013659

03/19/2026

DOI: 10.1371/journal.ppat.1013659

PMCID: PMC13012622

PMID: 41855156

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Abstract

Sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) restricts a broad spectrum of viruses through multifaceted mechanisms. It also limits spontaneous- and virus-induced innate immune responses by suppressing proinflammatory cytokine and type-I interferon (IFN-I) production. Some viruses escape SAMHD1 restriction and utilize SAMHD1-mediated innate immune suppression to establish effective infection through IFN antagonism. Our previous studies showed that SAMHD1 is a proviral factor facilitating replication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in human macrophages, monocytic THP-1 and epithelial-like HEK293T cell lines by suppressing IFN responses. However, it is unclear about the function of SAMHD1 in lung epithelial cells during SARS-CoV-2 infection. Here, we report that SAMHD1 knockout (KO) restricts SARS-CoV-2 replication in lung epithelial Calu-3 cells by suppressing endogenous expression of the viral receptor angiotensin-converting enzyme 2 (ACE2) via hepatocyte nuclear factor 1-alpha (HNF1α) and HNF1β. Using pseudotyped SARS-CoV-2 and lentiviral vectors, we found that SARS-CoV-2 spike protein-mediated viral entry was suppressed in SAMHD1 KO Calu-3 cells. SAMHD1 KO repressed ACE2 expression in Calu-3 cells at mRNA and protein levels. Functional analyses revealed that HNF1α and HNF1β were crucial for the endogenous ACE2 expression in Calu-3 cells. Additionally, SAMHD1 KO led to a reduction in the expression levels and ACE2-promoting function of HNF1α and HNF1β. Inhibition of IFN antiviral response by baricitinib, a Janus kinase 1 and 2 (JAK 1/2) inhibitor, did not revert the suppression of SARS-CoV-2 in SAMHD1 KO Calu-3 cells. SAMHD1 knock-in and deoxynucleoside supplementation experiments indicated that SAMHD1 expression and dNTP pool balance collectively regulated HNF1-mediated ACE2 expression in Calu-3 cells. Our findings demonstrate that SAMHD1 depletion hinders HNF1-mediated ACE2 expression and SARS-CoV-2 replication in Calu-3 cells via a novel mechanism beyond its IFN-suppressive function.

Details

Title: Subtitle: SAMHD1 depletion restricts SARS-CoV-2 infection by suppressing HNF1-dependent ACE2 expression in lung epithelial cells
Creators: Pak-Hin Hinson Cheung - University of Iowa, Microbiology and Immunology
Pearl Chan - University of Iowa
Hua Yang - University of Iowa
Krisztina Ambrus - Emory University
Shravya Honne - Emory University
Baek Kim - Emory University
Stanley Perlman - University of Iowa
Li Wu - University of Iowa
Resource Type: Journal article
Publication Details: PLoS pathogens, Vol.22(3), e1013659
DOI: 10.1371/journal.ppat.1013659
PMID: 41855156
PMCID: PMC13012622
NLM abbreviation: PLoS Pathog
ISSN: 1553-7374
eISSN: 1553-7374
Publisher: Public Library of Science
Grant note: R01 AI189220 / NIAID NIH HHS R21 AI181742 / NIAID NIH HHS
Language: English
Date published: 03/19/2026
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
Record Identifier: 9985147208202771

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