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Comment
. 2022 Jul;85(1):e21-e23.
doi: 10.1016/j.jinf.2022.04.019. Epub 2022 Apr 12.

Inhibition of endocytic recycling of ACE2 by SARS-CoV-2 S protein partially explains multiple COVID-19 related diseases caused by ACE2 reduction

Yongwen Ren  1 , Lu Lv  2 , Peng Li  2 , Leiliang Zhang  3
Affiliations
Comment

Inhibition of endocytic recycling of ACE2 by SARS-CoV-2 S protein partially explains multiple COVID-19 related diseases caused by ACE2 reduction

Yongwen Ren et al. J Infect. 2022 Jul.
No abstract available

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Conflict of interest statement

Declaration of Competing Interest The authors declare that there are no conflicts of interest.

Figures

Fig 1
Fig. 1
Endocytic recycling of ACE2 is mediated by SNX27. (A) Human ACE2 contains a SNX27 PDZ binding motif in the C-terminus. (B) Both SNX27 and its PDZ domain associate with ACE2 but not T803A/F805A mutant of ACE2 in GST pulldown experiments. Lysates from 293T cells transfected with the constructs expressing HA-tagged wild type hACE2 and T803A/F805A mutant of hACE2 were pulled down by GST–SNX27, GST-SNX27 PDZ or GST. Input represents 2% of total cell lysates. (C) Surface level of T803A/F805A mutant of ACE2 is weaker than that of wild type ACE2. HeLa cells transfected with the constructs expressing HA-tagged wild type hACE2 and T803A/F805A mutant of hACE2 were stained with HA antibody. ACE2-HA and T803A/F805A mutant of ACE2-HA are in red. Nucleus stained with DAPI is in Blue. Scale bar: 10 μM. Relative ACE2 intensity was normalized by quantifying at least 20 cells through Image J. ****, p value < 0.0001. (D) Silencing SNX27 by siRNA reduces surface level of ACE2. HeLa cells treated with siRNA against SNX27 for 3 days and then transfected with the construct expressing HA-tagged wild type hACE2 were stained with HA antibody. ACE2-HA is in red. Nucleus stained with DAPI is in Blue. Scale bar: 10 μM. Relative ACE2 intensity was normalized by quantifying at least 20 cells through Image J. ****, p value < 0.0001. HeLa cells were treated with siRNA against SNX27 for 3 days and then blotted with antibodies against SNX27 or β-actin.
Fig 2
Fig. 2
SARS-CoV-2 S protein reduces the surface level of ACE2 by associating with SNX27. (A) SARS-CoV-2 S protein contains a SNX27 binding motif in the C-terminus. (B) Both SNX27 and its PDZ domain associate with SARS-CoV-2 S. Lysates from 293T cells transfected with the constructs expressing GFP-tagged SARS-CoV-2 S were pulled down by GST–SNX27, GST-SNX27 PDZ or GST. Input represents 2% of total cell lysates. (C) Both SNX27 and its PDZ domain associate with SARS-CoV-2 S but not T1238A mutant of SARS-CoV-2 S in GST pulldown experiments. Lysates from 293T cells transfected with the constructs expressing GFP-tagged SARS-CoV-2 S or T1238A mutant of SARS-CoV-2 S were pulled down by GST–SNX27 or GST-SNX27 PDZ. Input represents 2% of total cell lysates. (D) SARS-CoV-2 S inhibits the interaction between ACE2 and SNX27 PDZ domain in GST pulldown experiments. Lysates from 293T cells transfected with the constructs expressing HA-tagged ACE2 with GFP-tagged SARS-CoV-2 S or GFP were pulled down by GST–SNX27 PDZ or GST. Input represents 2% of total cell lysates. (E) SARS-CoV-2 S suppresses the interaction between ACE2 and SNX27 in GST pulldown experiments. Lysates from 293T cells transfected with the constructs expressing HA-tagged ACE2 with GFP-tagged SARS-CoV-2 S or GFP were pulled down by GST–SNX27 or GST. Input represents 2% of total cell lysates. (F) SARS-CoV-2 S but not T1238A mutant of SARS-CoV-2 S inhibits the interaction between ACE2 and SNX27 PDZ domain in GST pulldown experiments. Lysates from 293T cells transfected with the constructs expressing HA-tagged ACE2 with GFP-tagged SARS-CoV-2 S, T1238A mutant of SARS-CoV-2 S, or GFP were pulled down by GST–SNX27 PDZ or GST. Input represents 2% of total cell lysates. (G) SARS-CoV-2 S but not T1238A mutant of SARS-CoV-2 S suppresses the interaction between ACE2 and SNX27 in GST pulldown experiments. Lysates from 293T cells transfected with the constructs expressing HA-tagged ACE2 with GFP-tagged SARS-CoV-2 S, T1238A mutant of SARS-CoV-2 S, or GFP were pulled down by GST–SNX27 or GST. Input represents 2% of total cell lysates. (H) Compared with GFP, GFP-S but not GSP-S-T1238A mutant reduces the surface level of ACE2. HeLa cells transfected with the constructs expressing HA-tagged ACE2 with GFP-tagged SARS-CoV-2 S, T1238A mutant of SARS-CoV-2 S, or GFP were stained with HA antibody. ACE2-HA is in red. SARS-CoV-2 S, T1238A mutant of SARS-CoV-2 S, and GFP are in green. Nucleus stained with DAPI is in Blue. Scale bar: 10 μM. Relative ACE2 intensity was normalized by quantifying at least 20 cells through Image J. ***, p value < 0.001; ****, p value < 0.0001. (I) Model of how SARS-CoV-2 S blocks ACE2 transport mediated by SNX27. Endocytic recycling of ACE2 is mediated by SNX27. SARS-CoV-2 S could inhibit plasma membrane targeting of ACE2 by suppressing the association of SNX27 and ACE2, leading to the reduction of ACE2.
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