Severe acute respiratory syndrome associated coronavirus type 1 (SARS-CoV-1) nucleoprotein (N) is mostly cytoplasmic but can localize to the nucleus (Timani KA et al. 2005; You J et al. 2005). In the nucleus, SARS-CoV-1 N protein potentiates transforming growth factor-beta (TGF-β)-induced SMAD-mediated expression of plasminogen activator inhibitor-1 (PAI-1, encoded by the SERPINE1 gene) (Zhao X et al. 2008). Under normal conditions, the plasma level of SERPINE1 is relatively low. The expression of SERPINE1 is regulated by the activated SMAD complex (SMAD3:SMAD4) (Dennler S et al. 1998; Stroschein SL et al. 1999) that binds to the promoter of the SERPINE1 gene together with the transcription factor SP1 (shown in mouse cells, Yuan H et al. 2013) and the histone acetyltransferase EP300 (p300) (Zhao X et al. 2008).
Upon SARS-CoV-1 infection, viral N associates with SMAD3 in human peripheral lung epithelial (HPL1) cells (Zhao X et al. 2008). The N binding to SMAD3 enhanced SMAD3:EP300 complex formation in human HEK293T cells. Chromatin immunoprecipitation (ChIP) assay showed the association of N and the SERPINE1 promoter in HPL1 cells that stably expressed N protein (Zhao X et al. 2008). The interaction between SARS-CoV-1 N and SMAD3 also prevented SMAD3 from complexing with SMAD4 (Zhao X et al. 2008).

Increased levels of active SERPINE1 may lead to coagulation dysfunctions which have been associated with an increased risk of ischemic cardiovascular events and tissue fibrosis (Ha H et al. 2009; ).