Proc Natl Acad Sci U S A . Nonmuscle myosin heavy chain IIA facilitates SARS-CoV-2 infection in human pulmonary cells

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Proc Natl Acad Sci U S A


. 2021 Dec 14;118(50):e2111011118.
doi: 10.1073/pnas.2111011118.
Nonmuscle myosin heavy chain IIA facilitates SARS-CoV-2 infection in human pulmonary cells


Jian Chen ^{1 2} , Jun Fan ² , Zhilu Chen ¹ , Miaomiao Zhang ² , Haoran Peng ³ , Jian Liu ² , Longfei Ding ² , Mingbin Liu ² , Chen Zhao ² , Ping Zhao ⁴ , Shuye Zhang ^{5 2} , Xiaoyan Zhang ^{5 2} , Jianqing Xu ^{5 2}



Affiliations

• PMID: 34873039
• DOI: 10.1073/pnas.2111011118

Free article

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), binds to host receptor angiotensin-converting enzyme 2 (ACE2) through its spike (S) glycoprotein, which mediates membrane fusion and viral entry. However, the expression of ACE2 is extremely low in a variety of human tissues, especially in the airways. Thus, other coreceptors and/or cofactors on the surface of host cells may contribute to SARS-CoV-2 infection. Here, we identified nonmuscle myosin heavy chain IIA (MYH9) as an important host factor for SARS-CoV-2 infection of human pulmonary cells by using APEX2 proximity-labeling techniques. Genetic ablation of MYH9 significantly reduced SARS-CoV-2 pseudovirus infection in wild type (WT) A549 and Calu-3 cells, and overexpression of MYH9 enhanced the pseudovirus infection in WT A549 and H1299 cells. MYH9 was colocalized with the SARS-CoV-2 S and directly interacted with SARS-CoV-2 S through the S2 subunit and S1-NTD (N-terminal domain) by its C-terminal domain (designated as PRA). Further experiments suggested that endosomal or myosin inhibitors effectively block the viral entry of SARS-CoV-2 into PRA-A549 cells, while transmembrane protease serine 2 (TMPRSS2) and cathepsin B and L (CatB/L) inhibitors do not, indicating that MYH9 promotes SARS-CoV-2 endocytosis and bypasses TMPRSS2 and CatB/L pathway. Finally, we demonstrated that loss of MYH9 reduces authentic SARS-CoV-2 infection in Calu-3, ACE2-A549, and ACE2-H1299 cells. Together, our results suggest that MYH9 is a candidate host factor for SARS-CoV-2, which mediates the virus entering host cells by endocytosis in an ACE2-dependent manner, and may serve as a potential target for future clinical intervention strategies.

Keywords: COVID-19; MYH9; SARS-CoV-2; pan-coronavirus; virus entry.