An “Old” protein with a new story: Coronavirus endoribonuclease is important for evading host antiviral defenses

Abstract

Here we review the evolving story of the coronavirus endoribonuclease (EndoU). Coronavirus EndoU is encoded within the sequence of nonstructural protein (nsp) 15, which was initially identified as a component of the viral replication complex. Biochemical and structural studies revealed the enzymatic nature of nsp15/EndoU, which was postulated to be essential for the unique replication cycle of viruses in the order Nidovirales. However, the role of nsp15 in coronavirus replication was enigmatic as EndoU-deficient coronaviruses were viable and replicated to near wild-type virus levels in fibroblast cells. A breakthrough in our understanding of the role of EndoU was revealed in recent studies, which showed that EndoU mediates the evasion of viral double-stranded RNA recognition by host sensors in macrophages. This new discovery of nsp15/EndoU function leads to new opportunities for investigating how a viral EndoU contributes to pathogenesis and exploiting this enzyme for therapeutics and vaccine design against pathogenic coronaviruses.

Highlights

• •

  We provide a historical perspective on the identification of coronavirus (CoV) nsp15 as an endoribonuclease (EndoU).

• •

  We review the structural and functional studies of the enzymatic properties of EndoU.

• •

  We describe studies that found a non-essential role of EndoU activity in CoV replication in immortalized fibroblast cells.

• •

  We describe the discovery that EndoU is essential in evasion of host antiviral defenses in macrophages and in vivo.