Figure 1

MERS-CoV structure, genome organisation, and replication

MERS-CoV encodes a large replicase-transcriptase polyprotein (rep1A and rep1B), which is processed into 16 non-structural proteins (nsp). These proteins are required for the formation of the replicase-transcription complex, for cleavage of the polyprotein, and for immune evasion. Structural proteins (spike [S], envelope [E], membrane [M], and nucleocapsid [N]) and accessory proteins (ORFs 3, 4a, 4b, 5, 8b) are encoded in the end third of the 3' end of the genome of the genome. MERS-CoV binds to its cellular receptor DPP4 via the S protein, which is processed by host proteases to expose a fusion peptide. The viral genome is then released into the cytoplasm, where it is translated on host ribosomes into rep1A and rep1B proteins. The polyprotein is cleaved by two viral-encoded proteases, encoded by nsp3 and nsp5. Proteins involved in genome and subgenome replication and transcription include nsp12 (the RNA-dependent RNA polymerase [RdRP]) and two associated proteins, nsp7 and nsp8.¹²⁷ Nsp13 (a helicase), nsp14 (which encodes an N7 methyltransferase and ExoN, a protein required for genome fidelity), and nsp16 (a 2'-O methyltransferase) are also necessary for optimal genomic and subgenomic RNA synthesis. MERS-CoV transcription involves the synthesis of subgenomic RNAs, which encode the structural and accessory proteins located at the 3' end of the genome. Subgenomic and genomic RNAs are co-terminal, sharing the same 5' leader and 3' sequences. Subgenomic RNAs code for structural and accessory proteins (ORF3, 4a, 4b, 5, and 8b). ORF8b is encoded within the N gene (marked with purple lines). These accessory proteins are believed to have immunoevasive properties, but are not essential for replication, and are variably deleted in human and camel virus isolates.128, 129, 130 Genomic replication occurs on membrane structures such as double membrane vesicles (DMVs), convoluted membranes (CM), and vesicle packets (VP), which are merged DMV¹³¹ that have been formed from the rough endoplasmic reticulum (RER) by the combined action of nsp3, nsp4, and nsp6 (lower right). After synthesis on replicase-transcription complexes, RNA is encapsidated by the N protein and transported to the ERGIC (endoplasmic reticulum–Golgi compartment), where budding into membranes containing the S, E, and M proteins occurs before release from the cell. 3CLPro=chymotrypsin-like protease. ExoN=exonuclease. MERS-CoV=Middle East respiratory syndrome coronavirus. MTase=methyltransferase. NendoU=nidoviral uridylate-specific endoribonuclease. NF-κB=nuclear factor κ-light-chain-enhancer of activated B cells. NTPase=nucleoside-triphosphatase. pp1a=polyprotein 1a. PLPro=papain-like protease.