. 2023 Jan 16;105995.
doi: 10.1016/j.isci.2023.105995. Online ahead of print.
SARS-CoV-2 N protein mediates intercellular nucleic acid dispersion, a feature reduced in Omicron

Jung-Lin Wu 1 , I-I Kuan 1 , Jing-You Guo 1 , Wei-Chia Hsu 1 , Wei-Chun Tang 2 , Hsin-Ju Chan 3 4 , Yu-Ju Chen 3 , Bi-Chang Chen 2 , Han-Chung Wu 5 , James C Liao 1



The coronavirus nucleocapsid (N) protein is known to bind to nucleic acids and facilitate viral genome encapsulation. Here we report that N protein can mediate RNA or DNA entering neighboring cells through ACE2-independent, receptor (STEAP2)-mediated endocytosis, and achieve gene expression. The effect is more pronounced for the N protein of wild-type SARS-CoV-2 than that of Omicron variant and other human coronaviruses. This effect is enhanced by RANTES (CCL5), a chemokine induced by N protein, and lactate, a metabolite produced in hypoxia, to cause more damage. These findings might explain the clinical observations in SARS-CoV-2-infected cases. Moreover, the N protein-mediated function can be inhibited by N protein-specific monoclonal antibodies or p38 mitogen-activated protein kinases inhibitors. Since the N-protein-mediated nucleic acid endocytosis involves a receptor commonly expressed in many types of cells, our findings suggest N protein may have an additional role in SARS-CoV-2 pathogenesis.

Keywords: COVID; Coronavirus; Omicron variant; SARS-CoV-2; nucleic acid delivery; nucleocapsid protein.