TY - JOUR
T1 - Targeting novel LSD1-dependent ACE2 demethylation domains inhibits SARS-CoV-2 replication
AU - Tu, Wen Juan
AU - McCuaig, Robert D.
AU - Melino, Michelle
AU - Rawle, Daniel J.
AU - Le, Thuy T.
AU - Yan, Kexin
AU - Suhrbier, Andreas
AU - Johnston, Rebecca L.
AU - Koufariotis, Lambros T.
AU - Waddell, Nicola
AU - Cross, Emily M.
AU - Tsimbalyuk, Sofiya
AU - Bain, Amanda
AU - Ahern, Elizabeth
AU - Collinson, Natasha
AU - Phipps, Simon
AU - Forwood, Jade K.
AU - Seddiki, Nabila
AU - Rao, Sudha
N1 - Funding Information:
We are grateful to all participants in this study. We thank Itaru Anraku for his assistance in managing the PC3 (BSL3) facility at QIMR Berghofer MRI and Alyssa Pye and Fredrick Moore (Queensland Health, Brisbane) for providing the SARS-CoV-2 virus. We would like to thank the QIMR Berghofer sequencing facility (particularly Paul Collins and Nadine Schulz), and the Genome Informatics team for enabling the RNA-seq. We thank Susan List-Armitage, Lisa Bowdler, and XiaoQing Chen (Sample Processing Service, QIMR) for assistance with patient blood collection. We thank Nigel Waterhouse (Microscope Facility, QIMR) for his assistance with the ANDOR WD Revolution super resolution microscopy and microscopy data analysis. We thank Melissa Caspar (Metagene/ASI) for her assistance with Digital Pathology ASI system. We thank Kirsten Spann for her contribution to the human bronchial epithelial cells experiment. We are also grateful to Corey Smith (Translational and Human Immunology laboratory, QIMR) for kindly providing flow cytometry resource used in this study and critical reading of the manuscript. The structural research was undertaken in part using the MX2 beamline at the Australian Synchrotron, part of ANSTO, and made use of the Australian Cancer Research Foundation (ACRF) detector. We would also like to thank the University of Queensland Protein Expression Facility for kindly providing the SARS-Cov-2 Spike Protein S1 (Glu14-Ser680). We also thank Sonja Plompen and Harry Clark (Mimotopes, Melbourne) for their expertise with peptide synthesis. A.S. is supported by Investigator grant (APP1173880) from the Health and Medical Research Council of Australia. We thank Clive Berghofer and Lyn Brazil (and others) for their generous philanthropic donations to help set up SARS-CoV-2 research at QIMR Berghofer MRI. We also like to thank Clive Berghofer and Lyn Brazil (and others) for their generous philanthropic donations providing research support for this study to the Rao lab at QIMR Berghofer MRI.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Treatment options for COVID-19 remain limited, especially during the early or asymptomatic phase. Here, we report a novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and the epigenetic eraser enzyme LSD1, and its interplay with the nuclear shuttling importin pathway. Recent studies have shown a critical role for the importin pathway in SARS-CoV-2 infection, and many RNA viruses hijack this axis to re-direct host cell transcription. LSD1 colocalized with ACE2 at the cell surface to maintain demethylated SARS-CoV-2 spike receptor-binding domain lysine 31 to promote virus–ACE2 interactions. Two newly developed peptide inhibitors competitively inhibited virus–ACE2 interactions, and demethylase access to significantly inhibit viral replication. Similar to some other predominantly plasma membrane proteins, ACE2 had a novel nuclear function: its cytoplasmic domain harbors a nuclear shuttling domain, which when demethylated by LSD1 promoted importin-α-dependent nuclear ACE2 entry following infection to regulate active transcription. A novel, cell permeable ACE2 peptide inhibitor prevented ACE2 nuclear entry, significantly inhibiting viral replication in SARS-CoV-2-infected cell lines, outperforming other LSD1 inhibitors. These data raise the prospect of post-exposure prophylaxis for SARS-CoV-2, either through repurposed LSD1 inhibitors or new, nuclear-specific ACE2 inhibitors.
AB - Treatment options for COVID-19 remain limited, especially during the early or asymptomatic phase. Here, we report a novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and the epigenetic eraser enzyme LSD1, and its interplay with the nuclear shuttling importin pathway. Recent studies have shown a critical role for the importin pathway in SARS-CoV-2 infection, and many RNA viruses hijack this axis to re-direct host cell transcription. LSD1 colocalized with ACE2 at the cell surface to maintain demethylated SARS-CoV-2 spike receptor-binding domain lysine 31 to promote virus–ACE2 interactions. Two newly developed peptide inhibitors competitively inhibited virus–ACE2 interactions, and demethylase access to significantly inhibit viral replication. Similar to some other predominantly plasma membrane proteins, ACE2 had a novel nuclear function: its cytoplasmic domain harbors a nuclear shuttling domain, which when demethylated by LSD1 promoted importin-α-dependent nuclear ACE2 entry following infection to regulate active transcription. A novel, cell permeable ACE2 peptide inhibitor prevented ACE2 nuclear entry, significantly inhibiting viral replication in SARS-CoV-2-infected cell lines, outperforming other LSD1 inhibitors. These data raise the prospect of post-exposure prophylaxis for SARS-CoV-2, either through repurposed LSD1 inhibitors or new, nuclear-specific ACE2 inhibitors.
UR - http://www.scopus.com/inward/record.url?scp=85106603988&partnerID=8YFLogxK
U2 - 10.1038/s41421-021-00279-w
DO - 10.1038/s41421-021-00279-w
M3 - Article
AN - SCOPUS:85106603988
SN - 2056-5968
VL - 7
SP - 1
EP - 21
JO - Cell Discovery
JF - Cell Discovery
IS - 1
M1 - 37
ER -