a | The single-stranded RNA (ssRNA) genomes of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) encode two large polyproteins, pp1a and pp1ab, which are proteolytically cleaved into 16 non-structural proteins (nsps), including papain-like protease (PLpro), 3C-like protease (3CLpro), RNA-dependent RNA polymerase (RdRp), helicase (Hel) and exonuclease (ExoN). An additional 9–12 ORFs are encoded through the transcription of a nested set of subgenomic RNAs. SARS-CoV and MERS-CoV form spherical particles that consist of four structural proteins. The envelope glycoprotein spike (S) forms a layer of glycoproteins that protrude from the envelope. Two additional transmembrane glycoproteins are incorporated in the virion: envelope (E) and membrane (M). Inside the viral envelope resides the helical nucleocapsid, which consists of the viral positive-sense RNA ((+)RNA) genome encapsidated by protein nucleocapsid (N). b | Following entry of the virus into the host cell, the viral RNA is uncoated in the cytoplasm. ORF1a and ORF1ab are translated to produce pp1a and pp1ab, which are cleaved by the proteases that are encoded by ORF1a to yield 16 nsps that form the RNA replicase–transcriptase complex. This complex localizes to modified intracellular membranes that are derived from the rough endoplasmic reticulum (ER) in the perinuclear region, and it drives the production of negative-sense RNAs ((−)RNAs) through both replication and transcription. During replication, full-length (−)RNA copies of the genome are produced and used as templates for full-length (+)RNA genomes. During transcription, a subset of 7–9 subgenomic RNAs, including those encoding all structural proteins, is produced through discontinuous transcription. In this process, subgenomic (−)RNAs are synthesized by combining varying lengths of the 3′ end of the genome with the 5′ leader sequence necessary for translation. These subgenomic (−)RNAs are then transcribed into subgenomic (+)mRNAs. Although the different subgenomic mRNAs may contain several ORFs, only the first ORF (that closest to the 5′ end) is translated. The resulting structural proteins are assembled into the nucleocapsid and viral envelope at the ER–Golgi intermediate compartment (ERGIC), followed by release of the nascent virion from the infected cell.