Meta-Biol

• Pathways

SARS-CoV-1 encodes eight subgenomic RNAs, mRNA2 to mRNA9. mRNA1 corresponds to the genomic RNA. The 5' and 3' ends of subgenomic RNAs are identical, in accordance with the template switch model of coronavirus RNA transcription (Snijder et al. 2003, Thiel et al. 2003, Yount et al. 2003). Genomic positive strand RNA is first transcribed into negative sense (minus strand) subgenomic mRNAs by template switching. Negative sense mRNAs subsequently serve as templates for the synthesis of positive strand subgenomic mRNAs. As shown in murine hepatitis virus (MHV), which is closely related to SARS-CoV-1, negative-sense viral RNAs are present in much smaller amounts than positive-sense RNAs (Irigoyen et al. 2016). Of the eight subgenomic mRNAs of SARS-CoV-1, mRNA2 encodes the S protein, mRNA3 is bicistronic and encodes proteins 3a and 3b, mRNA4 encodes the E protein, mRNA5 encodes the M protein, mRNA6 encodes protein 6, and bicistronic mRNA7, mRNA8 and mRNA9 encode proteins 7a and 7b (mRNA7), 8a and 8b (mRNA8), and 9a and N (mRNA9), respectively (Snijder et al. 2003, Thiel et al. 2003, Yount et al. 2003). The template switch model of coronavirus involves discontinuous transcription of subgenomic RNA, with the leader body joining occurring during the synthesis of minus strand RNAs. Each subgenomic RNA contains a leader transcription regulatory sequence (leader TRS) that is identical to the leader of the genome, appended via polymerase “jumping” during negative strand synthesis to the body transcription regulatory sequence (body TRS), a short, AU-rich motif of about 10 nucleotides found upstream of each ORF that is destined to become 5' proximal in one of the subgenomic mRNAs. The 3' and 5'UTRs may interact through RNA–RNA and/or RNA–protein plus protein–protein interactions to promote circularization of the coronavirus genome, placing the elongating minus strand in a favorable topology for leader-body joining. The host protein PABP was found to bind to the coronavirus 3' poly(A) tail and to interact with the host protein eIF-4G, a component of the three-subunit complex that binds to mRNA cap structures, which may promote the circularization of the coronavirus genome. Two viral proteins that bind to the coronavirus 5'UTR, the N protein and nsp1, may play a role in template switching. The poly(A) tail is necessary for the initiation of minus-strand RNA synthesis at the 3' end of genomic RNA. Elongation of nascent minus strand RNA continues until the first functional body TRS motif is encountered. A fixed proportion of replication-transcription complexes (RTCs) will either disregard the TRS motif and continue to elongate the nascent strand or stop synthesis of the nascent minus strand and relocate to the leader TRS, extending the minus strand by copying the 5' end of the genome. The completed minus-strand RNAs then serve as templates for positive strand mRNA synthesis (reviewed by Sawicki et al. 2007, Yang and Leibowitz 2015).

Infectious diseases are ones due to the presence of pathogenic microbial agents in human host cells. Processes annotated in this category include bacterial, viral and parasitic infection pathways.

Bacterial infection pathways currently include some metabolic processes mediated by intracellular Mycobacterium tuberculosis, the actions of clostridial, anthrax, and diphtheria toxins, and the entry of Listeria monocytogenes into human cells.

Viral infection pathways currently include the life cycles of SARS-CoV viruses, influenza virus, HIV (human immunodeficiency virus), and human cytomegalovirus (HCMV).

Parasitic infection pathways currently include Leishmania infection-related pathways.

Fungal infection pathways and prion diseases have not been annotated.

Biological processes are captured in Reactome by identifying the molecules (DNA, RNA, protein, small molecules) involved in them and describing the details of their interactions. From this molecular viewpoint, human disease pathways have three mechanistic causes: the inclusion of microbially-expressed proteins, altered functions of human proteins, or changed expression levels of otherwise functionally normal human proteins.

The first group encompasses the infectious diseases such as influenza, tuberculosis and HIV infection. The second group involves human proteins modified either by a mutation or by an abnormal post-translational event that produces an aberrant protein with a novel function. Examples include somatic mutations of EGFR and FGFR (epidermal and fibroblast growth factor receptor) genes, which encode constitutively active receptors that signal even in the absence of their ligands, or the somatic mutation of IDH1 (isocitrate dehydrogenase 1) that leads to an enzyme active on 2-oxoglutarate rather than isocitrate, or the abnormal protein aggregations of amyloidosis which lead to diseases such as Alzheimer's.

Infectious diseases are represented in Reactome as microbial-human protein interactions and the consequent events. The existence of variant proteins and their association with disease-specific biological processes is represented by inclusion of the modified protein in a new or variant reaction, an extension to the 'normal' pathway. Diseases which result from proteins performing their normal functions but at abnormal rates can also be captured, though less directly. Many mutant alleles encode proteins that retain their normal functions but have abnormal stabilities or catalytic efficiencies, leading to normal reactions that proceed to abnormal extents. The phenotypes of such diseases can be revealed when pathway annotations are combined with expression or rate data from other sources.

Depending on the biological pathway/process immediately affected by disease-causing gene variants, non-infectious diseases in Reactome are organized into diseases of signal transduction by growth factore receptors and second messengers, diseases of mitotic cell cycle, diseases of cellular response to stress, diseases of programmed cell death, diseases of DNA repair, disorders of transmembrane transporters, diseases of metabolism, diseases of immune system, diseases of neuronal system, disorders of developmental biology, disorders of extracellular matrix organization, and diseases of hemostatis.